DISI - User contributions [en]

Using Wynton

2019-08-06T17:46:17Z

Xiaobo wan:

Here is how to use Wynton with DOCK/ZINC

https://ucsf-hpc.github.io/wynton/status/index.html

* 1 get an account @ https://ucsf-hpc.github.io/wynton/about/join.html
* 2 login
$ '''ssh <username>@wynlog1.compbio.ucsf.edu'''
OR
$ '''$ ssh <username>@log2.wynton.ucsf.edu'''
* 3 here are the disks:
[benwong@wynlog1 ~]$ '''ls -lh /bks'''
total 93K
drwxr-xr-x. 8 root root 8 Oct 7 2018 ex1
drwxr-xr-x. 10 root root 10 Oct 7 2018 ex2
drwxr-xr-x. 19 root root 19 Oct 7 2018 ex3
drwxr-xr-x. 9 root root 9 Oct 7 2018 ex4
drwxr-xr-x. 14 root root 14 Oct 7 2018 ex5
drwxr-xr-x. 9 root root 9 Oct 7 2018 ex6
drwxr-xr-x. 8 root root 8 Jul 17 2018 ex7
drwxr-xr-x. 8 root root 8 May 3 2018 ex8
drwxr-xr-x. 10 root root 10 Jun 11 16:15 ex9
drwxrwxr-x. 67 42024 1010 4.0K Mar 15 15:18 soft
drwxr-xr-x. 46 root root 4.0K Sep 17 2018 work

NOTE: wynton uses automount. /bks will appear empty until you specifically ls the disk you want. ls /bks may appear blank but if you do ls /bks/soft or /bks/ex9, the disk should automatically mount when you list it. If it's not working, then something's wrong.

* 4 here is the script
updated by xiaobo wan (2019/7/26)
step1
login wynton (ssh <username>@wynlog1.compbio.ucsf.edu)
step2
reformat the database_index
cp -r /nfs/home/xiaobo/UCSF_scripts/2019-7-3-Wynton-accounts/scripts_for_runningjobs-on-wynton/step1-reformat-split_database_index/step1-reformat-split_database_index-version2.pl ./
cp -r /nfs/home/xiaobo/UCSF_scripts/2019-7-3-Wynton-accounts/scripts_for_runningjobs-on-wynton/step1-reformat-split_database_index/check-split.list.new ./
perl step1-reformat-split_database_index-version2.pl database_index
check the new database_index file
cat database_index.new | awk '{ print "if test -e " $1 "; then echo " $1"; fi"}'>run.sh
bash run.sh >>database_index.new.csh
step3
change the dock3.7 submit files
cp -r /nfs/home/xiaobo/UCSF_scripts/2019-7-3-Wynton-accounts/scripts_for_runningjobs-on-wynton/step2-submit-jobs/ ./
then change the position of kingbo to your username
get_dock_files.csh: cp -v /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/dock/* .
rundock.csh:/wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/get_dock_files.csh
subdock.csh:qsub -t 1-$dirnum /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/rundock.csh "$dock"
submit.csh:/wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/subdock.csh /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/dock.csh
step4
submit the job
python $DOCKBASE/docking/setup/setup_db2_zinc15_file_number.py ./ leads $database $num count
csh /wynton/home/shoichetlab/username/scripts/step2-submit-jobs/submit.csh
Notes:
you can change the runing time of job in file rundock.csh #$ -l h_rt=24:00:00
You disk space is only 1TB, check it!!!!!!
[[Category:Internal]]

Using Wynton

2019-07-26T18:54:09Z

Xiaobo wan:

Here is how to use Wynton with DOCK/ZINC

https://ucsf-hpc.github.io/wynton/status/index.html

* 1 get an account @ https://ucsf-hpc.github.io/wynton/about/join.html
* 2 login
$ '''ssh <username>@wynlog1.compbio.ucsf.edu'''
OR
$ '''$ ssh <username>@log2.wynton.ucsf.edu'''
* 3 here are the disks:
[benwong@wynlog1 ~]$ '''ls -lh /bks'''
total 93K
drwxr-xr-x. 8 root root 8 Oct 7 2018 ex1
drwxr-xr-x. 10 root root 10 Oct 7 2018 ex2
drwxr-xr-x. 19 root root 19 Oct 7 2018 ex3
drwxr-xr-x. 9 root root 9 Oct 7 2018 ex4
drwxr-xr-x. 14 root root 14 Oct 7 2018 ex5
drwxr-xr-x. 9 root root 9 Oct 7 2018 ex6
drwxr-xr-x. 8 root root 8 Jul 17 2018 ex7
drwxr-xr-x. 8 root root 8 May 3 2018 ex8
drwxr-xr-x. 10 root root 10 Jun 11 16:15 ex9
drwxrwxr-x. 67 42024 1010 4.0K Mar 15 15:18 soft
drwxr-xr-x. 46 root root 4.0K Sep 17 2018 work

NOTE: wynton uses automount. /bks will appear empty until you specifically ls the disk you want. ls /bks may appear blank but if you do ls /bks/soft or /bks/ex9, the disk should automatically mount when you list it. If it's not working, then something's wrong.

* 4 here is the script
updated by xiaobo wan (2019/7/26)
step1
login wynton (ssh <username>@wynlog1.compbio.ucsf.edu)
step2
reformat the database_index
cp -r /wynton/home/shoichetlab/kingbo/scripts/step1-reformat-split_database_index/step1-reformat-split_database_index-version2.pl ./
cp -r /wynton/home/shoichetlab/kingbo/scripts/step1-reformat-split_database_index/check-split.list.new ./
perl step1-reformat-split_database_index-version2.pl database_index
check the new database_index file
cat database_index.new | awk '{ print "if test -e " $1 "; then echo " $1"; fi"}'>run.sh
bash run.sh >>database_index.new.csh
step3
change the dock3.7 submit files
cp -r /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/ ./
then change the position of kingbo to username
get_dock_files.csh: cp -v /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/dock/* .
rundock.csh:/wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/get_dock_files.csh
subdock.csh:qsub -t 1-$dirnum /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/rundock.csh "$dock"
submit.csh:/wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/subdock.csh /wynton/home/shoichetlab/kingbo/scripts/step2-submit-jobs/dock.csh
step4
submit the job
python $DOCKBASE/docking/setup/setup_db2_zinc15_file_number.py ./ leads $database $num count
csh /wynton/home/shoichetlab/username/scripts/step2-submit-jobs/submit.csh
Notes:
you can change the runing time of job in file rundock.csh #$ -l h_rt=24:00:00
You disk space is only 1TB, check it!!!!!!
[[Category:Internal]]

Using Wynton

2019-07-26T18:44:28Z

Xiaobo wan:

Using Wynton

2019-07-26T18:37:24Z

Xiaobo wan:

DOCKovalent lysine inhibitor design tutorial

2019-04-11T16:52:57Z

Xiaobo wan: Created page with " This was written on April 4, 2018. This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018). These file ..."

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary product without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCK 3.7

2019-04-11T16:52:44Z

Xiaobo wan: /* For DOCKovalent, start here */

= About =

DOCK 3.7 the current version in the [[DOCK 3]] series of docking programs developed and used by the [[Shoichet Lab]]. Please read and cite the DOCK 3.7 paper
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

DOCK 3.7 is written in Fortran and some C. It is an update of [[DOCK 3.6]] with many improved features. DOCK 3.7 comes with all the tools necessary to prepare a
protein for docking and some tools necessary to build ligands, though some tools must be obtained externally. It uses new Flexibase/DB2 files found in [[ZINC15]]. It includes tools to prepare receptors, and several auxiliary scripts.

DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

{{TOCright}}

= Start here =
* [[So you want to set up a lab]] - only if you don't already have hardware ready.
* [[Install DOCK 3.7]]
* [[DOCK 3.7 2014/09/25 FXa Tutorial]]
* [[DOCK 3.7 2015/04/15 abl1 Tutorial]] superseded
* [[DOCK 3.7 2018/06/05 abl1 Tutorial]]
* [[DOCK 3.7 2016/09/16 Tutorial for Enrichment Calculations (Trent & Jiankun)]]
* [[DOCK 3.7 tutorial (Anat)]]
* [[DOCK 3.7 with GIST tutorials]]
* [[DOCK 3.7 tutorial based on Webinar 2017/06/28]]
* [[Getting started with DOCK 3.7]]
* [[Blastermaster]] - Prepare input for and then run [[DOCK 3.7]].
* [[Ligand preparation 3.7]] - Create dockable databases for [[DOCK 3.7]].
* [[Ligand preparation]] - different version.
* [[Ligand prep Irwin Nov 2016]] - John's current version
* [[Mol2db2 Format 2]] - details on the database formate.
* [[Running docking 3.7]] - how to actually run docking.
* [[DOCK 3.7 Development]] - for software developers
=== For DOCKovalent, start here ===
* [[DOCKovalent_3.7]]
* [[DOCKovalent lysine inhibitor design tutorial]]
* [[DOCKovalent cysteine inhibitor design tutorial]]

= Prepare Receptor =
* [[Protein Target Preparation]]
* [[Using_thin_spheres_in_DOCK3.7]]
* [[Adding Static Waters to the Protein Structure]]
* [[Flexible Docking]]
* [[Visualize docking grids]]
* [[Minimize protein-ligand complex with AMBER]]
* [[Minimize protein-covalent ligand complex with AMBER]]

= Prepare Screening Library =
* [[mol2db2]] is the program that creates [[mol2db2 format]] database files which are read by [[DOCK 3.7]]
* [[ligand preparation 3.7]]
* [[generating decoys (Reed's way)]]

= Running Docking =
* [[Running docking 3.7]] - JJI currently working on this.
* [[Running DOCK 3.7]] - this seems to be slightly dated.
* [[INDOCK 3.7]] - file format used by [[DOCK 3.7]]
* [[DOCK3.7_INDOCK_Minimization_Parameter]] - How to run DOCK 3.7.1rc1 (and latter versions) with the minimization.
* Interpreting the [[OUTDOCK 3.7]] file.

= Analysis =
* [[Analyzing DOCK Results]]
* [http://autodude.docking.org/ Auto-DUD-E Test Set] (external site)
* [[Other Useful Stuff]]
* [[Bootstrap AUC]]

= Post Docking Clustering=
* [[How to process results from a large-scale docking]]
* [[Large-scale SMILES Requesting and Fingerprints Converting]]
* [[ECFP4 Best First Clustering]]
* [[Bemis-Murcko Scaffold Analysis]]

= Post Docking Filters=
* [[Large-scale TC Calculations]]
* [[Whole Library TC to Knowns Calculations]]
* [[Filtering ligands for novelty]]
= Redocking with Enhanced Sampling =
*[[Sample Additional Ring Puckers ]]
= Rescoring =
*[[Rescoring_with_DOCK_3.7]]

= Available Libraries =
* [[ZINC Subset DB2 file locations]]
* how to get db2 files from zinc15.docking.org

= Analog by Catalog=
* [[Substructure searching]]
* [[TC analog searching in ZINC]]

= Previous verisons and compatibility =
DOCK 3.7 is part of the [[DOCK 3]] series. It differs substantially from its immediate predecessor [[DOCK 3.6]],
which uses a different format of database files that cannot be read by [[DOCK 3.7]], and vice versa.

= How to Cite =
To cite the DOCK 3.7 paper, please use
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

= How to Download =
DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

= Implementation =
DOCK 3.7 is written in Fortran and some C. Scripts are mostly in [[python]] and [[perl]].

{{Template:CC-BY-SA-30}}
{{Template:Coleman}}

[[Category:DOCK 3.7]]
[[Category:Software]]
[[Category:Freecom]]

DOCKovalent lysine inihibitor design tutorial

2019-04-11T16:51:36Z

DOCK 3.7

2019-04-11T16:49:37Z

Xiaobo wan: /* For DOCKovalent, start here */

= About =

DOCK 3.7 the current version in the [[DOCK 3]] series of docking programs developed and used by the [[Shoichet Lab]]. Please read and cite the DOCK 3.7 paper
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

DOCK 3.7 is written in Fortran and some C. It is an update of [[DOCK 3.6]] with many improved features. DOCK 3.7 comes with all the tools necessary to prepare a
protein for docking and some tools necessary to build ligands, though some tools must be obtained externally. It uses new Flexibase/DB2 files found in [[ZINC15]]. It includes tools to prepare receptors, and several auxiliary scripts.

DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

{{TOCright}}

= Start here =
* [[So you want to set up a lab]] - only if you don't already have hardware ready.
* [[Install DOCK 3.7]]
* [[DOCK 3.7 2014/09/25 FXa Tutorial]]
* [[DOCK 3.7 2015/04/15 abl1 Tutorial]] superseded
* [[DOCK 3.7 2018/06/05 abl1 Tutorial]]
* [[DOCK 3.7 2016/09/16 Tutorial for Enrichment Calculations (Trent & Jiankun)]]
* [[DOCK 3.7 tutorial (Anat)]]
* [[DOCK 3.7 with GIST tutorials]]
* [[DOCK 3.7 tutorial based on Webinar 2017/06/28]]
* [[Getting started with DOCK 3.7]]
* [[Blastermaster]] - Prepare input for and then run [[DOCK 3.7]].
* [[Ligand preparation 3.7]] - Create dockable databases for [[DOCK 3.7]].
* [[Ligand preparation]] - different version.
* [[Ligand prep Irwin Nov 2016]] - John's current version
* [[Mol2db2 Format 2]] - details on the database formate.
* [[Running docking 3.7]] - how to actually run docking.
* [[DOCK 3.7 Development]] - for software developers
=== For DOCKovalent, start here ===
* [[DOCKovalent_3.7]]
* [[DOCKovalent lysine inihibitor design tutorial]]
* [[DOCKovalent cysteine inhibitor design tutorial]]

= Prepare Receptor =
* [[Protein Target Preparation]]
* [[Using_thin_spheres_in_DOCK3.7]]
* [[Adding Static Waters to the Protein Structure]]
* [[Flexible Docking]]
* [[Visualize docking grids]]
* [[Minimize protein-ligand complex with AMBER]]
* [[Minimize protein-covalent ligand complex with AMBER]]

= Prepare Screening Library =
* [[mol2db2]] is the program that creates [[mol2db2 format]] database files which are read by [[DOCK 3.7]]
* [[ligand preparation 3.7]]
* [[generating decoys (Reed's way)]]

= Running Docking =
* [[Running docking 3.7]] - JJI currently working on this.
* [[Running DOCK 3.7]] - this seems to be slightly dated.
* [[INDOCK 3.7]] - file format used by [[DOCK 3.7]]
* [[DOCK3.7_INDOCK_Minimization_Parameter]] - How to run DOCK 3.7.1rc1 (and latter versions) with the minimization.
* Interpreting the [[OUTDOCK 3.7]] file.

= Analysis =
* [[Analyzing DOCK Results]]
* [http://autodude.docking.org/ Auto-DUD-E Test Set] (external site)
* [[Other Useful Stuff]]
* [[Bootstrap AUC]]

= Post Docking Clustering=
* [[How to process results from a large-scale docking]]
* [[Large-scale SMILES Requesting and Fingerprints Converting]]
* [[ECFP4 Best First Clustering]]
* [[Bemis-Murcko Scaffold Analysis]]

= Post Docking Filters=
* [[Large-scale TC Calculations]]
* [[Whole Library TC to Knowns Calculations]]
* [[Filtering ligands for novelty]]
= Redocking with Enhanced Sampling =
*[[Sample Additional Ring Puckers ]]
= Rescoring =
*[[Rescoring_with_DOCK_3.7]]

= Available Libraries =
* [[ZINC Subset DB2 file locations]]
* how to get db2 files from zinc15.docking.org

= Analog by Catalog=
* [[Substructure searching]]
* [[TC analog searching in ZINC]]

= Previous verisons and compatibility =
DOCK 3.7 is part of the [[DOCK 3]] series. It differs substantially from its immediate predecessor [[DOCK 3.6]],
which uses a different format of database files that cannot be read by [[DOCK 3.7]], and vice versa.

= How to Cite =
To cite the DOCK 3.7 paper, please use
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

= How to Download =
DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

= Implementation =
DOCK 3.7 is written in Fortran and some C. Scripts are mostly in [[python]] and [[perl]].

{{Template:CC-BY-SA-30}}
{{Template:Coleman}}

[[Category:DOCK 3.7]]
[[Category:Software]]
[[Category:Freecom]]

GPCR Waiver Wire

2019-02-24T16:49:36Z

Xiaobo wan: /* Project waiver order: */

THIS SEEMS DEAD, BUT CAN EASILY BE REVIVED.

When new projects come into the lab, the person on the top of the order gets first choice to either take or pass the project. The project will be moved down the order until it is claimed. Once a person claims a project, they will be moved to the bottom of the order. This process ideally ensures a fair process for determining who gets new projects and allows those that don't speak up as much to have a fair chance of getting a new, great project. Passing on a project will not effect the position in the order since not all projects are suitable for all persons.

'''Brian reserves the right to change the order at any time for any reason, e.g. passing on too many projects, new member in lab getting bumped up, etc...'''

== Updated guidelines: ==
a. People get first refusal for projects in the order they are listed. If they choose and are placed on a project they go to the bottom of the list.

b. Occasionally projects will come along where Brian feels someone has particular expertise or history. Brian reserves the right to over-rule the waiver list order in these circumstances.

c. On the GPCR projects teams have worked out very well. There must be a more senior partner and a more junior partner in these collaborations, if only because there is only one first co-first author. To encourage collaboration, anyone who volunteers to be the more junior partner in a project will not lose their place on the waiver list. Please discuss with the senior partner first to ensure compatibility.

----

== Project waiver order: ==

*Shuo Gu
*Jiankun Lyu
*Ying Yang
*Shiming Peng
*Chase Webb
*Brian Bender
*Stefan Gahbauer
*Reed Stein
*Xiaobo Wan
*Isha Singh
*Matt O'Meara
*Anat Levit

[[Category:Obsolete]]

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T01:02:24Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=

ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step2-1-combine-check-job.sh lib1
Input file :
1) the ligand library folder name (lib1)

extract the docking poses (you can also use your own scripts to process your data)

bash step2-3-rank-poses.sh lib1
Input file :
1) the ligand library folder name (lib1)

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring

First, extract the each pose

perl step1-split-poses.pl uniq.analysis.hqVA-M-ASF.dat.pdb

the protonation state of each linker after when using the chimera to add hydrogen
prepare the list for each linker containing charge information (default:0)

bash qsub_run_automatic_pipeline_for_amber_minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-C000032628502-1-5 0
INDOCK.bump1000000000000.pose1000.20.5.5-C000032628502-1-5 is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

==Step 8 8-pose-benchmark-systems==
From paper 1 the https://code.google.com/archive/p/covalentdock/downloads

76 systems (have't tested yet)

From Schrondinger covalent datasets 38 systems

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:44:08Z

Xiaobo wan: /* Step 6 Run the minimization and MM/GBSA rescoreing */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=

ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step2-1-combine-check-job.sh lib1
Input file :
1) the ligand library folder name (lib1)

extract the docking poses (you can also use your own scripts to process your data)

bash step2-3-rank-poses.sh lib1
Input file :
1) the ligand library folder name (lib1)

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring

First, extract the each pose

perl step1-split-poses.pl uniq.analysis.hqVA-M-ASF.dat.pdb

the protonation state of each linker after when using the chimera to add hydrogen
prepare the list for each linker containing charge information (default:0)

bash qsub_run_automatic_pipeline_for_amber_minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-C000032628502-1-5 0
INDOCK.bump1000000000000.pose1000.20.5.5-C000032628502-1-5 is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:13:06Z

Xiaobo wan: /* Step 5 Analysis and combine the top1 pose from different structures */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=

ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step2-1-combine-check-job.sh lib1
Input file :
1) the ligand library folder name (lib1)

extract the docking poses (you can also use your own scripts to process your data)

bash step2-3-rank-poses.sh lib1
Input file :
1) the ligand library folder name (lib1)

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:12:40Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=

ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step2-1-combine-check-job.sh lib1
Inputfile :
1) the ligand library folder name (lib1)

extract the docking poses (you can also use the your own scripts to process your data)

bash step2-3-rank-poses.sh lib1

Input file :
1) the ligand library folder name (lib1)

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:03:43Z

Xiaobo wan: /* Step 4 run the covalent docking in gimel */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=

ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:03:26Z

Xiaobo wan: /* Step 4 run the covalent docking in gimel */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file qsub_fix-pipeline-for-dock-and-filter.sh

scriptsdir=
ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-19T00:02:19Z

Xiaobo wan: /* Step 4 run the covalent docking in gimel */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter (exclusion criteria that ligands should form hydrogen bonds with the protein, and the ligand should form one hydrogen bond with protein)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the covalent modified cys in this file )

Define in the file
scriptsdir=qsub_fix-pipeline-for-dock-and-filter.sh
ligdir=

Input file :
1) the list different structure folders (4iqA-A-AR6)
2) the ligand library folder name (lib1)
bash qsub_fix-pipeline-for-dock-and-filter.sh run.list lib1

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T23:51:30Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T23:49:52Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_rigid 1000000000000.0
number_save 100
number_write 100
molecules_maximum 100000
electrostatic_scale 1.0
vdw_scale 1.0
bond_len 1.77
bond_ang1 124.18
bond_ang2 120.84
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T23:46:29Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different cysteine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-cys-rotamers
find the modification cys number in the PDB
echo "4iqy-A-AR6 A 104">>cys.list
bash step0_prepare_build_system.sh 4iqy-A-AR6
In the window of chimera, select all of the 3 cysteine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format CYS-4iqy-A-AR6.pdb
Then, to generate all 3 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash ../step1_run_build_system.sh 4iqy-A-AR6
results
4iqA-A-AR6 0 contacts
4iqB-A-AR6 0 contacts
4iqC-A-AR6 1 contacts
4iqA-A-AR6 O3' 16.951
4iqB-A-AR6 O3' 16.951
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 4iqA-A-AR6 box_margin(6) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T23:14:06Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

for a single smile (single-smile-generation) addSiH3-to-dimethylamino-acrylamide
python addSiH3-to-dimethylamino-acrylamide.py input-ligand.smi
python step3-remove_doubles.py addSiH3.smi
file file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/single-smile-generation/no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:22:07Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:21:36Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:20:36Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation
library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:20:20Z

Xiaobo wan: /* Step 1. Custom Ligand and Library Generation */

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation
cd 1-Custom-Ligand-Library-Generation
library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:20:00Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-18T22:19:36Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

library 1: search the acrylamide in the ZINC15 database (ask John to put your builded library in ZINC15)
login into http://zinc15.docking.org/patterns/home/, search acrylamide in pattern
found 1: Acrylamide-Terminal, [CD1]=[CD2]-C(=O)-[NX3] Purchase is 84576
File: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acrylamide/library1-70587-ZINC15-acrylamide-library.smi
db2 file in /mnt/nfs/ex9/work/xiaobo/new_covalent_lib/acrylamides/lib1

library 2: aldehyde-based-cyanoacrylamides
Search the aldehyde from ZINC15, and only-single-aldehyde-aromatic-for-sale+bb.smi 145960
one step synthesis
python aldehyde-to-cyanoacryl.py only-single-aldehyde-aromatic-for-sale+bb.smi
python step3-remove_doubles.py reaction_nocorina_out.ism
File:
/nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/aldehyde-based-cyanoacrylamides/145956-aldehyde-based-cyanoacrylamides.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/new_covalent_lib/2017-6-8-cyanoacrylamide

library 3: ~184,900 Enamine acids + Boc-diamine + acrylic acid library
filter3-selected_acids_2150.smi the most common 2150 Enamine acids fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python step1-SN1-diamines-CO2H.py filter3-selected_acids_2150.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file: /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/acids-Boc-acrylic-acid/final-acids-Boc-acrylic-acid.smi 184900
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-acids-Boc-acrylic-acid/acd2

library 4: ~145,508 Sulfonyl Chloride + Boc-diamine + acrylaic acid library
filter4-1677.sulfonyl_chlorides.smi the most common 1677 Enamine sulfonyl_chlorides fro Enamine
83-Boc_diamines.smi the most common 83 Boc from Enamine
two step synthesis
python SN1-diamines-CO2H.py filter4-1677.sulfonyl_chlorides.smi 83-Boc_diamines.smi
python step2-reaction-acrylic-acid.py in.smi
pyton step3-remove_doubles.py in2.smi
final file : /nfs/home/xiaobo/UCSF_scripts/2018-7-17-covalent_cys_wiki-tutorial/1-Custom-Ligand-Library-Generation/sulfonyl_chloride_Boc-acrylic-acid/final-sulfonyl_chloride_Boc-acrylic-acid.smi
db2 file in /mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc1
/mnt/nfs/ex7/work/xiaobo/2017-6-30-sulfonyl_chloride_Boc-acrylic-acid/suc2

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This script will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent cysteine inhibitor design tutorial

2018-07-17T19:47:55Z

DOCK 3.7

2018-07-17T19:40:02Z

Xiaobo wan:

= About =

DOCK 3.7 the current version in the [[DOCK 3]] series of docking programs developed and used by the [[Shoichet Lab]]. Please read and cite the DOCK 3.7 paper
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

DOCK 3.7 is written in Fortran and some C. It is an update of [[DOCK 3.6]] with many improved features. DOCK 3.7 comes with all the tools necessary to prepare a
protein for docking and some tools necessary to build ligands, though some tools must be obtained externally. It uses new Flexibase/DB2 files found in [[ZINC15]]. It includes tools to prepare receptors, and several auxiliary scripts.

DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

{{TOCright}}

= Start here =
* [[So you want to set up a lab]] - only if you don't already have hardware ready.
* [[Install DOCK 3.7]]
* [[DOCK 3.7 2014/09/25 FXa Tutorial]]
* [[DOCK 3.7 2015/04/15 abl1 Tutorial]] superseded
* [[DOCK 3.7 2018/06/05 abl1 Tutorial]]
* [[DOCK 3.7 2016/09/16 Tutorial for Enrichment Calculations (Trent & Jiankun)]]
* [[DOCK 3.7 tutorial (Anat)]]
* [[DOCK 3.7 with GIST tutorials]]
* [[DOCK 3.7 tutorial based on Webinar 2017/06/28]]
* [[Getting started with DOCK 3.7]]
* [[Blastermaster]] - Prepare input for and then run [[DOCK 3.7]].
* [[Ligand preparation 3.7]] - Create dockable databases for [[DOCK 3.7]].
* [[Ligand preparation]] - different version.
* [[Ligand prep Irwin Nov 2016]] - John's current version
* [[Mol2db2 Format 2]] - details on the database formate.
* [[Running docking 3.7]] - how to actually run docking.
* [[DOCK 3.7 Development]] - for software developers
=== For DOCKovalent, start here ===
* [[DOCKovalent_3.7]]
* [[DOCKovalent linker design tutorial]]
* [[DOCKovalent cysteine inhibitor design tutorial]]

= Prepare Receptor =
* [[Protein Target Preparation]]
* [[Adding Static Waters to the Protein Structure]]
* [[Flexible Docking]]
* [[Visualize docking grids]]
* [[Minimize protein-ligand complex with AMBER]]

= Prepare Screening Library =
* [[mol2db2]] is the program that creates [[mol2db2 format]] database files which are read by [[DOCK 3.7]]
* [[ligand preparation 3.7]]
* [[generating decoys (Reed's way)]]

= Running Docking =
* [[Running docking 3.7]] - JJI currently working on this.
* [[Running DOCK 3.7]] - this seems to be slightly dated.
* [[INDOCK 3.7]] - file format used by [[DOCK 3.7]]
* [[DOCK3.7_INDOCK_Minimization_Parameter]] - How to run DOCK 3.7.1rc1 (and latter versions) with the minimization.
* Interpreting the [[OUTDOCK 3.7]] file.

= Analysis =
* [[Analyzing DOCK Results]]
* [http://autodude.docking.org/ Auto-DUD-E Test Set] (external site)
* [[Other Useful Stuff]]

= Post Docking Clustering=
* [[How to process results from a large-scale docking]]
* [[Large-scale SMILES Requesting and Fingerprints Converting]]
* [[ECFP4 Best First Clustering]]
* [[Bemis-Murcko Scaffold Analysis]]

= Post Docking Filters=
* [[Large-scale TC Calculations]]
* [[Whole Library TC to Knowns Calculations]]
= Redocking with Enhanced Sampling =
*[[Sample Additional Ring Puckers ]]
= Rescoring =
*[[Rescoring_with_DOCK_3.7]]

= Available Libraries =
* [[ZINC Subset DB2 file locations]]
* how to get db2 files from zinc15.docking.org

= Analog by Catalog=
* [[Substructure searching]]
* [[TC analog searching in ZINC]]

= Previous verisons and compatibility =
DOCK 3.7 is part of the [[DOCK 3]] series. It differs substantially from its immediate predecessor [[DOCK 3.6]],
which uses a different format of database files that cannot be read by [[DOCK 3.7]], and vice versa.

= How to Cite =
To cite the DOCK 3.7 paper, please use
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

= How to Download =
DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

= Implementation =
DOCK 3.7 is written in Fortran and some C. Scripts are mostly in [[python]] and [[perl]].

{{Template:CC-BY-SA-30}}
{{Template:Coleman}}

[[Category:DOCK 3.7]]
[[Category:Software]]
[[Category:Freecom]]

DOCKovalent linker design tutorial

2018-06-18T20:08:55Z

DOCK 3.7

2018-06-18T20:07:30Z

Xiaobo wan: /* For DOCKovalent, start here */

= About =

DOCK 3.7 the current version in the [[DOCK 3]] series of docking programs developed and used by the [[Shoichet Lab]]. Please read and cite the DOCK 3.7 paper
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

DOCK 3.7 is written in Fortran and some C. It is an update of [[DOCK 3.6]] with many improved features. DOCK 3.7 comes with all the tools necessary to prepare a
protein for docking and some tools necessary to build ligands, though some tools must be obtained externally. It uses new Flexibase/DB2 files found in [[ZINC15]]. It includes tools to prepare receptors, and several auxiliary scripts.

DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

{{TOCright}}

= Start here =
* [[So you want to set up a lab]] - only if you don't already have hardware ready.
* [[Install DOCK 3.7]]
* [[DOCK 3.7 2014/09/25 FXa Tutorial]]
* [[DOCK 3.7 2015/04/15 abl1 Tutorial]] superseded
* [[DOCK 3.7 2018/06/05 abl1 Tutorial]]
* [[DOCK 3.7 2016/09/16 Tutorial for Enrichment Calculations (Trent & Jiankun)]]
* [[DOCK 3.7 tutorial (Anat)]]
* [[DOCK 3.7 with GIST tutorials]]
* [[DOCK 3.7 tutorial based on Webinar 2017/06/28]]
* [[Getting started with DOCK 3.7]]
* [[Blastermaster]] - Prepare input for and then run [[DOCK 3.7]].
* [[Ligand preparation 3.7]] - Create dockable databases for [[DOCK 3.7]].
* [[Ligand preparation]] - different version.
* [[Ligand prep Irwin Nov 2016]] - John's current version
* [[Mol2db2 Format 2]] - details on the database formate.
* [[Running docking 3.7]] - how to actually run docking.
* [[DOCK 3.7 Development]] - for software developers
=== For DOCKovalent, start here ===
* [[DOCKovalent_3.7]]
* [[DOCKovalent linker design tutorial]]

= Prepare Receptor =
* [[Protein Target Preparation]]
* [[Adding Static Waters to the Protein Structure]]
* [[Flexible Docking]]
* [[Visualize docking grids]]
* [[Minimize protein-ligand complex with AMBER]]

= Prepare Screening Library =
* [[mol2db2]] is the program that creates [[mol2db2 format]] database files which are read by [[DOCK 3.7]]
* [[ligand preparation 3.7]]
* [[generating decoys (Reed's way)]]

= Running Docking =
* [[Running docking 3.7]] - JJI currently working on this.
* [[Running DOCK 3.7]] - this seems to be slightly dated.
* [[INDOCK 3.7]] - file format used by [[DOCK 3.7]]
* [[DOCK3.7_INDOCK_Minimization_Parameter]] - How to run DOCK 3.7.1rc1 (and latter versions) with the minimization.
* Interpreting the [[OUTDOCK 3.7]] file.

= Analysis =
* [[Analyzing DOCK Results]]
* [http://autodude.docking.org/ Auto-DUD-E Test Set] (external site)
* [[Other Useful Stuff]]

= Post Docking Clustering=
* [[How to process results from a large-scale docking]]
* [[Large-scale SMILES Requesting and Fingerprints Converting]]
* [[ECFP4 Best First Clustering]]
* [[Bemis-Murcko Scaffold Analysis]]

= Post Docking Filters=
* [[Large-scale TC Calculations]]
* [[Whole Library TC to Knowns Calculations]]

= Available Libraries =
* [[ZINC Subset DB2 file locations]]
* how to get db2 files from zinc15.docking.org

= Analog by Catalog=
* [[Substructure searching]]
* [[TC analog searching in ZINC]]

= Previous verisons and compatibility =
DOCK 3.7 is part of the [[DOCK 3]] series. It differs substantially from its immediate predecessor [[DOCK 3.6]],
which uses a different format of database files that cannot be read by [[DOCK 3.7]], and vice versa.

= How to Cite =
To cite the DOCK 3.7 paper, please use
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

= How to Download =
DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

= Implementation =
DOCK 3.7 is written in Fortran and some C. Scripts are mostly in [[python]] and [[perl]].

{{Template:CC-BY-SA-30}}
{{Template:Coleman}}

[[Category:DOCK 3.7]]
[[Category:Software]]
[[Category:Freecom]]

DOCKovalent linker design tutoral

2018-04-06T00:21:40Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-06T00:20:50Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-06T00:19:26Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary product without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-06T00:17:56Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary product without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-06T00:16:51Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MM/GBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T19:51:29Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 pose from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:14:00Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==

cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results

bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results

bash step3_combine-best-energy.sh structure-list lib1

Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==

cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)
save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:11:25Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare
1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:10:39Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:10:04Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:09:15Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
results
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:08:34Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:07:13Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism
input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /nfs/soft/dock/versions/dock37/DOCK-3.7-beta9-min
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:06:34Z

Xiaobo wan:

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi

reaction2:
python step2-reaction-SF-meta.py scaffold.ism

input file: scaffold.ism is the primary products without the SF
output file: final_scaffold1.smi

reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /nfs/soft/dock/versions/dock37/DOCK-3.7-beta9-min
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

==Step 3 modify the INDOCK parameters for saving multiple poses ==

cd 3-modify-the-INDOCK-parameters
change the default parameters for covalent docking

bump_maximum 100
bump_rigid 100
number_save 1000
number_write 1000
molecules_maximum 100000
bond_len 1.61
bond_ang1 121.02
bond_ang2 107.36
len_range 0.0
len_step 0.1
ang1_range 20.0
ang2_range 20.0
ang1_step 5
ang2_step 5
check_clashes no
per_atom_scores yes

==Step 4 run the covalent docking in gimel==
cd 4-run-the-covalent-docking

contain a pharmacophore filter ( exclusion criteria that ligands should form hydrogen bonds with the kinase hinge region, and the shared pyrimidine 3-aminopyrazole scaffold should be within 2 Å compared to the crystal conformation)

Prepare 1)the modified INDOCK file INDOCK.bump1000000000000.pose1000.20.5.5
2)the gate residue file (define the two residue in the SRC kinase domain MET341 VAL399)
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)
bash /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_cys_wiki-tutorial/4-run-the-covalent-docking/qsub_multipe_jobs structure-list lib1 lib1.list

==Step 5 Analysis and combine the top1 poses from different structures==
cd 5-Analysis-and-combine-the-top1-poses-from-different-structures
after the covalent docking, analyze the docking results
bash step1_extract_the_best_score.sh structure-list lib1 lib1.list
Inputfile :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
3) the linker name list (lib1.list)

combine the docking results
bash step3_combine-best-energy.sh structure-list lib1
Input file :
1) the list different structure folders (5K9A-B-X44,5K9A-C-X44)
2) the ligand library folder name (lib1)
Output file:
1)sort.final.combine-new.aura-A-X63.list.dat rank all of the top1 pose for each linker
2)submit.new.aura-A-X63.list.dat the name of structure file and linker

==Step 6 Run the minimization and MMGBSA rescoreing==
cd 6-Run-the-minimization-and-MMGBSA-rescoring
First, check the protonation state of each linker after when using the chimera to add hydrogen
second, the different H position of linkers will result in the different labelling number of the attached NH of lysine residue
prepare the list for each linker containing these two informations in XO44.charge.list file (default:xabs 1 1)

bash step7_fix_prolem_resubmit_MMPBSA.minimization.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB
INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB is the folder for runing minimization

after minimization, then run the AMBER MMGBSA rescoring
bash step10_fix_prolem_resubmit_MMPBSA_score.sh INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB

extract the scoring number for each linker
bash step6_resubmit.extract_GBscore.sh list
the list contains (INDOCK.bump1000000000000.pose1000.20.5.5-xo4E-A-X44-X44-meta-xaaa-1-mini_end_GB)

==Step 7 analyze the final pose by chimera==
cd 7-analyze-the-final-pose-by-chimera
first sort the linker according to the MMGBSA score
cat MMGBSA.list | sort -nk 2 >sort.MMGBSA.list

1-extract the pose without the protein
perl fix-step3_extract_best_score_combinepdb_after_minimize.pl sort.MMGBSA.list
2-extract the pose with the protein
perl fix-step4_extract_best_score_combinepdb_after_minimize_with_rec.pl sort.MMGBSA.list

using the chimera to visualize these poses and select the final linker (save to PDB file)

save the linker viewdock state: P
perl step0-filter_by_the_chimera.pl pdb to extract the final poses

DOCKovalent linker design tutoral

2018-04-05T03:04:06Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-05T03:01:28Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-04T16:34:12Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-04T16:26:07Z

Xiaobo wan:

DOCKovalent linker design tutoral

2018-04-04T16:22:28Z

Xiaobo wan: Created page with "These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial ==Step 1. Custom Ligand and Library Generation == 1/Custom Ligand / Library Ge..."

These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial

==Step 1. Custom Ligand and Library Generation ==
1/Custom Ligand / Library Generation
cd 1-Custom-Ligand-Library-Generation
For meta-SF library building

reaction1:

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi
scaffod.smi is the smile of the scaffold for reaction
817.zinc.list.smi is the smile of collecte 817 different diamine linkers
reaction2:
python step2-reaction-SF-meta.py scaffold.ism
inputfile: scaffold.ism is the primary products without the SF
outputfile: final_scaffold1.smi
reaction3: remove the doubles
python step3-remove_doubles.py final_scaffold1.smi
inputfile:final_scaffold1.smi
outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking
log into gimel
setenv DOCKBASE /nfs/soft/dock/versions/dock37/DOCK-3.7-beta9-min
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

==Step 2 Protein preparation (different lysine rotamers) ==
2/Protein preparation (different lysine rotamers)
cd 2-Protein-preparation-different-lysine-rotamers
find the modification lys number in the PDB
echo "5K9I-B-X44 B 295">>lys.list
bash step0_prepare_build_system.sh 5K9I-B-X44
in the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
bash step1_run_build_system.sh 5K9I-B-X44
5K9E-B-X44 SBH 2.038
5K9B-B-X44 SBH 2.321
5K9I-B-X44 OBI 2.949
5K9L-B-X44 SBH 4.683
5K9R-B-X44 OBI 4.925
Each folder contains rec.pdb and xtal-lig.pdb

For each folder
bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
box_margin is defined from the center of the xtal-lig.pdb file

DOCK 3.7

2018-04-04T16:16:08Z

Xiaobo wan: /* For DOCKovalent, start here */

= About =

DOCK 3.7 the current version in the [[DOCK 3]] series of docking programs developed and used by the [[Shoichet Lab]]. Please read and cite the DOCK 3.7 paper
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

DOCK 3.7 is written in Fortran and some C. It is an update of [[DOCK 3.6]] with many improved features. DOCK 3.7 comes with all the tools necessary to prepare a
protein for docking and some tools necessary to build ligands, though some tools must be obtained externally. It uses new Flexibase/DB2 files found in [[ZINC15]]. It includes tools to prepare receptors, and several auxiliary scripts.

DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

{{TOCright}}

= Start here =
* [[So you want to set up a lab]] - only if you don't already have hardware ready.
* [[Install DOCK 3.7]]
* [[DOCK 3.7 2014/09/25 FXa Tutorial]]
* [[DOCK 3.7 2015/04/15 abl1 Tutorial]]
* [[DOCK 3.7 2016/09/16 Tutorial for Enrichment Calculations (Trent & Jiankun)]]
* [[DOCK 3.7 tutorial (Anat)]]
* [[DOCK 3.7 with GIST tutorials]]
* [[DOCK 3.7 tutorial based on Webinar 2017/06/28]]
* [[Getting started with DOCK 3.7]]
* [[Blastermaster]] - Prepare input for and then run [[DOCK 3.7]].
* [[Ligand preparation 3.7]] - Create dockable databases for [[DOCK 3.7]].
* [[Ligand preparation]] - different version.
* [[Ligand prep Irwin Nov 2016]] - John's current version
* [[Mol2db2 Format 2]] - details on the database formate.
* [[Running docking 3.7]] - how to actually run docking.
* [[DOCK 3.7 Development]] - for software developers
=== For DOCKovalent, start here ===
* [[DOCKovalent_3.7]]
* [[DOCKovalent linker design tutoral]]

= Prepare Receptor =
* [[Protein Target Preparation]]
* [[Adding Static Waters to the Protein Structure]]
* [[Flexible Docking]]
* [[Visualize docking grids]]
* [[Minimize protein-ligand complex with AMBER]]

= Prepare Screening Library =
* [[mol2db2]] is the program that creates [[mol2db2 format]] database files which are read by [[DOCK 3.7]]
* [[ligand preparation 3.7]]
* [[generating decoys (Reed's way)]]

= Running Docking =
* [[Running docking 3.7]] - JJI currently working on this.
* [[Running DOCK 3.7]] - this seems to be slightly dated.
* [[INDOCK 3.7]] - file format used by [[DOCK 3.7]]
* [[DOCK3.7_INDOCK_Minimization_Parameter]] - How to run DOCK 3.7.1rc1 (and latter versions) with the minimization.
* Interpreting the [[OUTDOCK 3.7]] file.

= Analysis =
* [[Analyzing DOCK Results]]
* [http://autodude.docking.org/ Auto-DUD-E Test Set] (external site)
* [[Other Useful Stuff]]

= Post Docking Clustering=
* [[How to process results from a large-scale docking]]
* [[Large-scale SMILES Requesting and Fingerprints Converting]]
* [[ECFP4 Best First Clustering]]
* [[Bemis-Murcko Scaffold Analysis]]

= Post Docking Filters=
* [[Large-scale TC Calculations]]

= Available Libraries =
* [[ZINC Subset DB2 file locations]]
* how to get db2 files from zinc15.docking.org

= Analog by Catalog=
* [[Substructure searching]]
* [[TC analog searching in ZINC]]

= Previous verisons and compatibility =
DOCK 3.7 is part of the [[DOCK 3]] series. It differs substantially from its immediate predecessor [[DOCK 3.6]],
which uses a different format of database files that cannot be read by [[DOCK 3.7]], and vice versa.

= How to Cite =
To cite the DOCK 3.7 paper, please use
[http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075992 Coleman, Carchia, Sterling, Irwin & Shoichet, PLOS ONE 2013.]

= How to Download =
DOCK 3.7 is available at [http://dock.compbio.ucsf.edu/DOCK3.7/ http://dock.compbio.ucsf.edu/DOCK3.7/].

= Implementation =
DOCK 3.7 is written in Fortran and some C. Scripts are mostly in [[python]] and [[perl]].

{{Template:CC-BY-SA-30}}
{{Template:Coleman}}

[[Category:DOCK 3.7]]
[[Category:Software]]
[[Category:Freecom]]