Generating decoys (Reed's way): Difference between revisions
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source /nfs/soft/jchem/current/env.csh | source /nfs/soft/jchem/current/env.csh | ||
== Querying ZINC for Protomers == | |||
This procedure is advised if you want decoys to be charge-matched to ligands. | |||
=== Step 1) Setting up | === Step 1) Setting up directories for Protomers === | ||
Before starting, you need a SMILES file with the format (SMILES first, ID second): | Before starting, you need a SMILES file with the format (SMILES first, ID second): | ||
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You also need an input file named "decoy_generation.in" with the following lines: | You also need an input file named "decoy_generation.in" with the following lines: | ||
PROTONATE YES | PROTONATE YES | ||
MWT 125 | MWT 20 125 | ||
LOGP 3.6 | LOGP 0.4 3.6 | ||
RB 5 | RB 1 5 | ||
HBA 4 | HBA 0 4 | ||
HBD 3 | HBD 0 3 | ||
CHARGE 2 | CHARGE 0 2 | ||
DECOYS PER LIGAND 50 | DECOYS PER LIGAND 50 | ||
If your SMILES file is already protonated as you want it, set "PROTONATE NO" | Notice that this is not the same "decoy_generation.in" as for "Generating Decoys with SMILES" | ||
If your SMILES file is already protonated as you want it, set "PROTONATE NO". | |||
This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties: | This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties: | ||
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- within +/- 2 charge | - within +/- 2 charge | ||
- 0.35 or less Tanimoto | - 0.35 or less Tanimoto | ||
These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands. | These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands. | ||
For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have. | For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have. | ||
Once you have created this file, run the following command to create the decoy generation directory: | Once you have created this file, run the following command to create the decoy generation directory: | ||
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"ligand_${number}" for each of the ligands in the SMILES file you input. | "ligand_${number}" for each of the ligands in the SMILES file you input. | ||
=== Step 2) Retrieving | === Step 2) Retrieving protomer decoys from ZINC15 === | ||
If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command: | If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command: | ||
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Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input. | Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input. | ||
=== Step 3) Removing | === Step 3) Removing protomer decoys that are too similar to known ligands === | ||
To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, | To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, | ||
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This will run on the queue. | This will run on the queue. | ||
=== Step 4) Assigning accepted | === Step 4) Assigning accepted protomer decoys to each ligand protomer === | ||
Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys | Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys | ||
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This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors. | This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors. | ||
=== Step 5) | === Step 5) Copying decoy .db2.gz files into your directories === | ||
To copy property-matched decoys into your own directory of choice, run the following command: | |||
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0004_copy_decoys_to_new_dir.py {NEW_DIR_NAME} {COPY_TO_DIR} | |||
SMILES for decoys | where {COPY_TO_DIR} is a new directory that will be created where your decoys will be copied into. In this directory, two subdirectories will be created: | ||
"ligands" - this will include "ligands.smi" which includes all the SMILES strings that have at least 50 property matched decoys | |||
"decoys" - this will include the decoy .db2.gz files for docking and "decoys.smi" which contains all the SMILES strings for property matched decoys | |||
IMPORTANT: It is possible that there were not 50 property-matched decoys for all of your ligand protomers. The "ligands.smi" file in {COPY_TO_DIR} will not include these. Make | |||
sure you do not dock these if you calculate enrichment values. | |||
== Querying ZINC for | == Querying ZINC for SMILES == | ||
If you would like to query ZINC for decoy SMILES so that you can build decoys yourself or if your ligands are >400 Da, continue here. If not, go to "Querying ZINC for Protomers" | |||
=== Step 1) Setting up | === Step 1) Setting up SMILES directory === | ||
Before starting, you need a SMILES file with the format (SMILES first, ID second): | Before starting, you need a SMILES file with the format (SMILES first, ID second): | ||
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You also need an input file named "decoy_generation.in" with the following lines: | You also need an input file named "decoy_generation.in" with the following lines: | ||
SMILES YES | |||
PROTONATE YES | PROTONATE YES | ||
MWT | MWT 125 | ||
LOGP | LOGP 3.6 | ||
RB | RB 5 | ||
HBA | HBA 4 | ||
HBD | HBD 3 | ||
CHARGE | CHARGE 2 | ||
DECOYS PER LIGAND 50 | DECOYS PER LIGAND 50 | ||
GENERATE DECOYS 750 | |||
If your SMILES file is already protonated as you want it, set "PROTONATE NO". "SMILES" tells the function you want to query ZINC for SMILES, not built protomers. | |||
If your SMILES file is already protonated as you want it, set "PROTONATE NO". | |||
This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties: | This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties: | ||
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- within +/- 2 charge | - within +/- 2 charge | ||
- 0.35 or less Tanimoto | - 0.35 or less Tanimoto | ||
"GENERATE DECOYS" specifies how many potential decoys you want to check for property matching with your ligands. A smaller number results in faster decoy generation, but a smaller pool of potential decoys to compare your ligand against. A larger number results in slower decoy generation, and greater likelihood of property-matched decoys for all your ligands. | |||
These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands. | These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands. | ||
For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have. | For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have. | ||
Once you have created this file, run the following command to create the decoy generation directory: | Once you have created this file, run the following command to create the decoy generation directory: | ||
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"ligand_${number}" for each of the ligands in the SMILES file you input. | "ligand_${number}" for each of the ligands in the SMILES file you input. | ||
=== Step 2) Retrieving | === Step 2) Retrieving SMILES decoys from ZINC15 === | ||
If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command: | If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command: | ||
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Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input. | Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input. | ||
=== Step 3) Removing | === Step 3) Removing SMILES decoys that are too similar to known ligands === | ||
To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, | To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, | ||
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This will run on the queue. | This will run on the queue. | ||
=== Step 4) Assigning accepted | === Step 4) Assigning accepted SMILES decoys to each ligand protomer === | ||
Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys | Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys | ||
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This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors. | This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors. | ||
=== Step 5) | === Step 5) Setting up ligand/decoy directories for building SMILES === | ||
To | If you have queried ZINC for SMILES, you need to build the decoys yourself. To write the SMILES file, run the following command: | ||
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0004b_write_out_ligands_decoys.py {NEW_DIR_NAME} {COPY_TO_DIR} | |||
SMILES for decoys can now be built. | |||
*** Note that building decoys can generate multiple protomers for the same ligand. This may result in docking decoys that were not property matched to your ligands. A script to identify the correct decoy protomer is under construction. | |||
== Visualizing Decoy Properties == | == Visualizing Decoy Properties == | ||
Revision as of 01:12, 7 February 2019
Written by Reed Stein on April 3, 2018.
This pipeline will generate property-matched decoys for a ligand SMILES file, and will copy decoy .db2.gz files into a directory for you. To build ligands yourself, see "ligand prep" in:
http://wiki.docking.org/index.php/DOCK_3.7_tutorial_%28Anat%29
All scripts for this tutorial can be found in:
/mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/
Before running any scripts, make sure to source the current version of Python
source /nfs/soft/python/envs/complete/current/env.csh
Additionally, JChem needs to be sourced in your ~/.cshrc file with the command:
source /nfs/soft/jchem/current/env.csh
Querying ZINC for Protomers
This procedure is advised if you want decoys to be charge-matched to ligands.
Step 1) Setting up directories for Protomers
Before starting, you need a SMILES file with the format (SMILES first, ID second):
S(Nc1c(O)cc(C(=O)O)cc1)(c2c(scc2)C(=O)O)(=O)=O 116
You also need an input file named "decoy_generation.in" with the following lines:
PROTONATE YES MWT 20 125 LOGP 0.4 3.6 RB 1 5 HBA 0 4 HBD 0 3 CHARGE 0 2 DECOYS PER LIGAND 50
Notice that this is not the same "decoy_generation.in" as for "Generating Decoys with SMILES"
If your SMILES file is already protonated as you want it, set "PROTONATE NO".
This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties:
- within 125 Daltons
- within 3.6 logP
- within 5 rotatable bonds
- within 4 hydrogen bond acceptors
- within 3 hydrogen bond donors
- within +/- 2 charge
- 0.35 or less Tanimoto
These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands.
For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have.
Once you have created this file, run the following command to create the decoy generation directory:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0000_protonate_setup_dirs.py {SMILES_FILE} {NEW_DIR_NAME}
Provide a directory name that you want in place of {NEW_DIR_NAME}. This will create the directory with subdirectories named "ligand_${number}" for each of the ligands in the SMILES file you input.
Step 2) Retrieving protomer decoys from ZINC15
If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0001_qsub_generate_decoys.py {NEW_DIR_NAME}
Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input.
Step 3) Removing protomer decoys that are too similar to known ligands
To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0002_remove_similar_compounds.py {NEW_DIR_NAME}
This will run on the queue.
Step 4) Assigning accepted protomer decoys to each ligand protomer
Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys to the ligand protomers. Make sure you have the "decoy_generation_input.in" file from before in {NEW_DIR_NAME}.
To filter the decoys, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0003_qsub_filter_decoys.py {NEW_DIR_NAME}
This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors.
Step 5) Copying decoy .db2.gz files into your directories
To copy property-matched decoys into your own directory of choice, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0004_copy_decoys_to_new_dir.py {NEW_DIR_NAME} {COPY_TO_DIR}
where {COPY_TO_DIR} is a new directory that will be created where your decoys will be copied into. In this directory, two subdirectories will be created:
"ligands" - this will include "ligands.smi" which includes all the SMILES strings that have at least 50 property matched decoys
"decoys" - this will include the decoy .db2.gz files for docking and "decoys.smi" which contains all the SMILES strings for property matched decoys
IMPORTANT: It is possible that there were not 50 property-matched decoys for all of your ligand protomers. The "ligands.smi" file in {COPY_TO_DIR} will not include these. Make sure you do not dock these if you calculate enrichment values.
Querying ZINC for SMILES
If you would like to query ZINC for decoy SMILES so that you can build decoys yourself or if your ligands are >400 Da, continue here. If not, go to "Querying ZINC for Protomers"
Step 1) Setting up SMILES directory
Before starting, you need a SMILES file with the format (SMILES first, ID second):
S(Nc1c(O)cc(C(=O)O)cc1)(c2c(scc2)C(=O)O)(=O)=O 116
You also need an input file named "decoy_generation.in" with the following lines:
SMILES YES PROTONATE YES MWT 125 LOGP 3.6 RB 5 HBA 4 HBD 3 CHARGE 2 DECOYS PER LIGAND 50 GENERATE DECOYS 750
If your SMILES file is already protonated as you want it, set "PROTONATE NO". "SMILES" tells the function you want to query ZINC for SMILES, not built protomers.
This file specifies that for each ligand protomer, 50 decoys will be retrieved with the following properties:
- within 125 Daltons
- within 3.6 logP
- within 5 rotatable bonds
- within 4 hydrogen bond acceptors
- within 3 hydrogen bond donors
- within +/- 2 charge
- 0.35 or less Tanimoto
"GENERATE DECOYS" specifies how many potential decoys you want to check for property matching with your ligands. A smaller number results in faster decoy generation, but a smaller pool of potential decoys to compare your ligand against. A larger number results in slower decoy generation, and greater likelihood of property-matched decoys for all your ligands.
These are the default values, but you can input your desired minimum and maximum values that decoys can differ by, relative to the ligands.
For "DECOYS PER LIGAND", input the number of decoys that each ligand protomer should have.
Once you have created this file, run the following command to create the decoy generation directory:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0000_protonate_setup_dirs.py {SMILES_FILE} {NEW_DIR_NAME}
Provide a directory name that you want in place of {NEW_DIR_NAME}. This will create the directory with subdirectories named "ligand_${number}" for each of the ligands in the SMILES file you input.
Step 2) Retrieving SMILES decoys from ZINC15
If you have edited the "decoy_generation.in" file which is now located in {NEW_DIR_NAME} as you want, you can run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0001_qsub_generate_decoys.py {NEW_DIR_NAME}
Jobs will run 5 at a time until completed. This should take a few hours, depending on how many ligands you input.
Step 3) Removing SMILES decoys that are too similar to known ligands
To remove any decoys retrieved that are too similar to all the ligands you have retrieved decoys for, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0002_remove_similar_compounds.py {NEW_DIR_NAME}
This will run on the queue.
Step 4) Assigning accepted SMILES decoys to each ligand protomer
Now that the previous script has removed any decoys that were too similar to known ligands, we can assign the remaining decoys to the ligand protomers. Make sure you have the "decoy_generation_input.in" file from before in {NEW_DIR_NAME}.
To filter the decoys, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0003_qsub_filter_decoys.py {NEW_DIR_NAME}
This will run on the queue. A log file called "FILTER_DECOYS.log" will be generated in {NEW_DIR_NAME} with information and any errors.
Step 5) Setting up ligand/decoy directories for building SMILES
If you have queried ZINC for SMILES, you need to build the decoys yourself. To write the SMILES file, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0004b_write_out_ligands_decoys.py {NEW_DIR_NAME} {COPY_TO_DIR}
SMILES for decoys can now be built.
- Note that building decoys can generate multiple protomers for the same ligand. This may result in docking decoys that were not property matched to your ligands. A script to identify the correct decoy protomer is under construction.
Visualizing Decoy Properties
Visualizing property distributions
To visualize the distributions of molecular properties of matched decoys relative to the ligands, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0005_plot_properties.py {NEW_DIR_NAME}
There will be 6 images in {NEW_DIR_NAME} for molecular weight, logP, number of rotatable bonds, number of hydrogen bond donors, number of hydrogen bond acceptors, and net charge of ligands and decoys.
Visualizing decoy Tanimotos to ligands
To visualize how different the matched decoys are to the input ligands, run the following command:
python /mnt/nfs/home/rstein/zzz.scripts/DUDE_SCRIPTS/0006_plot_tanimoto_to_lig.py {NEW_DIR_NAME}
There will be a box and whisker plot image in {NEW_DIR_NAME} showing the Tanimotos calculated between each ligand and all decoys.