DOCK Blaster:Tutorial 1: Difference between revisions

From DISI
Jump to navigation Jump to search
No edit summary
Line 19: Line 19:


Hippocampal mineralocorticoid receptors play a major role in the control of the hypothalamus-pituitary-adrena (HPA) axis, and thus MR is a target for drug discovery.
Hippocampal mineralocorticoid receptors play a major role in the control of the hypothalamus-pituitary-adrena (HPA) axis, and thus MR is a target for drug discovery.
 


= Preliminary Results =  
= Preliminary Results =  
We will attempt to use DOCK Blaster to answer these questions, using data that has been prepared in advance. If you wish to use DOCK Blaster on your own project, you must prepare data to conform with [[DOCK Blaster:Input Preparation | DOCK Blaster's]] basic requirements. To do this tutorial, please carefully follow the steps below. This tutorial usually takes about two hours, but most of the time is simply waiting for the computers to do the work on our servers.
We will attempt to use DOCK Blaster to answer these questions, using data that has been prepared in advance. If you wish to use DOCK Blaster on your own project, you must prepare the data yourself. See [[DOCK Blaster:Input Preparation | Input Preparation]] for details.


== Protocol 1 - aquire target structure and prepare input files ==
== Protocol P1 - Acquire target structure and prepare input files ==
 
* P1.1. Go to the benchmarking data page [http://data.docking.org/ data.docking.org] and browse the DUD40 set, selecting the [http://data.docking.org/dud40/mr/ MR set]. Download each of these five files. On windows, you do this by right mouse clicking and selecting "save link as". If you are using your own target, you must prepare the files yourself (see [[DOCK Blaster:Input Preparation | Input Preparation]]).
* 1. Go to the benchmarking data page [http://data.docking.org/ data.docking.org] and select the DUD40 set, and then the [http://data.docking.org/dud40/mr/ MR set]. Download each of these five files (e.g. by right mouse clicking on them if you are in windows).  


[[Image:DBtut1_1f.jpg|thumb|right|Figure T1.1 - Prepare input and launch job]]
[[Image:DBtut1_1f.jpg|thumb|right|Figure T1.1 - Prepare input and launch job]]


* 2. Go to the [http://blaster.docking.org | DOCK Blaster page] and select [http://blaster.docking.org/start.shtml | Queue A Job] from the DOCK! pull down menu (Figure T1.1).
== Protocol P2 - Submit job and review preliminary results ==
 
* P2.1. Go to the [http://blaster.docking.org | DOCK Blaster main page] and select [http://blaster.docking.org/start.shtml | Queue A Job] from the DOCK! pull down menu (Figure T1.1). Fill in the form as in the figure, as follows.  
* 3. Fill in the form as follows.  
** a. In the "Target" field, select the receptor, rec.pdb.
** 5. In the next field "docked ligand" select the xtal-lig.mol2 file.
** b. In the next field, select "Docked ligand" and select the ligand, xtal-lig.mol2.
** 6. Optionally, you may select the actives.smi and inactives.smi from the next two lines.  
** c. In the "Actives" field, select the actives.smi file.
** 7. Enter your email address if you wish to receive progress reports by email.
** d. In the "Inactives" field, select the inactives.smi file.
** 8. Enter a brief comment about the calculation.  
** e. In "Email for reports", enter your email address (optional).
** 9. (optional: enter cofactor.par below)
** f. In the "Aim of this experiment" field, write a short memo about what you are doing.
** g. Check your input, and click "DOCK!" when you are ready.  


If you have followed the steps above, your screen should now look something like Figure Tut1-1 (right).
If you have followed the steps above, your screen should now look something like Figure Tut1-1 (right).
[[Image:DBtut1_2f.jpg|thumb|right|Figure T1.2 - Scrutinizer - data are uploaded, checked, and the job is started].


* P2.2. Depending on available system resources, your job is now either running, or queued to run when a slot becomes available. If your screen does not look like Figure T1.2, check the input and try again. If the job is still failing after the third attempt, please write to support at docking.org for assistance.


** 10. Click on "DOCK" to upload the files and begin docking. You will be taken to the "Submission Scrutinizer", as depicted in Figure Tut1-2.
* P2.3. Read what is reported by the Scrutinizer (Figure T1.2), and proceed to the Job Watcher by clicking on the link at the bottom of the page when you are ready.


* P2.4. You should now be in the Job Watcher (Figure T1.3). Depending on how much time has elapsed, and how busy our cluster is, you will see a progress report of the current status of your job. As time passes, the yellow status indicator should progress from left to right  indicating the progress of your job through Target Preparation and Calibration.  [[Image:DBtut1_3f.jpg|thumb|right|Figure T1.3]]


** 11. Your job should now be running. If it is not, there is either some part of the above instructions you did not follow, or we are currently experiencing problems with our systems.
* P2.5. If all goes as usual, your job will have completed within an hour. You may reload the Job Watcher at any time to get an updated status report of your job. When calibration is complete, you may review the preliminary results and decide on the next course of action.  


** 12. Read through the submission scrutinizer, and go to the Job Watcher by clicking on the link at the bottom of the page... http://blaster.docking.org/cgi-bin/jobmon.pl
* P2.6 Review Calibration results. blah blah blah.


** 13. You should now be in the Job Watcher. Depending on how much time has elapsed, and how busy our cluster is, you will see a progress report of your job. It might look something like Figure Tut1-3. [[Image:DBtut1_3f.jpg|thumb|right|Figure T1.3]]
[[Image:DBtut1_4f.jpg|thumb|right|Figure T1.4]]
 
** 14. If all goes well, the job will complete in about an hour. You may reload the page at anytime to get updated status of the job progress.
 
** 15. Preliminary docking normally begins after the site preparation is complete, often about 15 minutes after you first submitted the job. Once preliminary docking results are available, new links appear in the job watcher to allow you to start to see docked ligands. Caution: until the preliminary docking is complete, it can be misleading to rely upon incomplete preliminary docking results to reach any conclusions about the docking results.


[[Image:DBtut1_4f.jpg|thumb|right|Figure T1.4]]


== Examining the Results ==
= Proposed Research =  
Preliminary results above show that docking is able to enrich known actives from among a database of decoys. This suggests that prospective docking for discovery of novel ligands is reasonable and can be expected to suggest interesting compounds to test.


== Docking a Database ==
== Protocol P3. Dock the "fragment-like" purchasable compounds from ZINC ==


== Browsing and interpreting the results ==  
== Protocol P4. Review and interpret fragment docking results ==  


== Follow up and variations ==
== Protocol P5. Follow up calculations and variations ==


== Possible problems and alternative approaches ==
== Possible problems and alternative approaches ==
= Research Plan =


= Literature Cited =  
= Literature Cited =  
We refer you to our publications pages for theory and practice of docking and virtual screening.
* [[Publications:DOCK]]
* [[Publications:ZINC]]
* [[Publications:DUD]]
* [[Publications:Reviews_and_opinion]]
* [[Publications:Targets]]


 
Document status: working tutorial. Please correct any errors you may find.
 
 
 
 


[[Category:DOCK Blaster]]
[[Category:DOCK Blaster]]
[[Category:Tutorials]]
[[Category:Tutorials]]

Revision as of 18:56, 27 November 2007

DOCK Blaster Tutorial 1. Dock to Mineralocorticoid receptor A DOCK Blaster Tutorial.

Mineralocorticoid receptor, PDB 2aa2

Specific Aims

This tutorial will show you how to retrospectively dock a crystallographically observed ligand, aldosterone, into the human mineralocorticoid receptor, PDB code 2aa2. You will also dock a list of annotated actives from the literature, as well as property-matched decoys. Finally, you will prospectively dock the ZINC "fragment-like" library into MR, and pick compounds to test as possible binders. The questions are:

  • 1. Can DOCK Blaster re-dock the native ligand close to its crystallographically observed position, with a competitive score?
  • 2. Can DOCK Blaster enrich known actives from a database of property-matched decoys?
  • 3. Can DOCK Blaster suggest novel, commercially available ligands for MR?
Aldostereone, the crystallographically observed ligand of MR in PDB 2aa2

Background and Significance

Mineralocorticoid receptor (MR) is a receptor with high affinity for mineralocorticoids. It belongs to the steroid hormone receptor family where the ligand diffuses into cells, interacts with the receptor and results in a single transduction affecting specific gene expression in the nucleus. see Wikipedia.

Hippocampal mineralocorticoid receptors play a major role in the control of the hypothalamus-pituitary-adrena (HPA) axis, and thus MR is a target for drug discovery.

Preliminary Results

We will attempt to use DOCK Blaster to answer these questions, using data that has been prepared in advance. If you wish to use DOCK Blaster on your own project, you must prepare the data yourself. See Input Preparation for details.

Protocol P1 - Acquire target structure and prepare input files

  • P1.1. Go to the benchmarking data page data.docking.org and browse the DUD40 set, selecting the MR set. Download each of these five files. On windows, you do this by right mouse clicking and selecting "save link as". If you are using your own target, you must prepare the files yourself (see Input Preparation).
Figure T1.1 - Prepare input and launch job

Protocol P2 - Submit job and review preliminary results

  • P2.1. Go to the | DOCK Blaster main page and select | Queue A Job from the DOCK! pull down menu (Figure T1.1). Fill in the form as in the figure, as follows.
    • a. In the "Target" field, select the receptor, rec.pdb.
    • b. In the next field, select "Docked ligand" and select the ligand, xtal-lig.mol2.
    • c. In the "Actives" field, select the actives.smi file.
    • d. In the "Inactives" field, select the inactives.smi file.
    • e. In "Email for reports", enter your email address (optional).
    • f. In the "Aim of this experiment" field, write a short memo about what you are doing.
    • g. Check your input, and click "DOCK!" when you are ready.

If you have followed the steps above, your screen should now look something like Figure Tut1-1 (right). [[Image:DBtut1_2f.jpg|thumb|right|Figure T1.2 - Scrutinizer - data are uploaded, checked, and the job is started].

  • P2.2. Depending on available system resources, your job is now either running, or queued to run when a slot becomes available. If your screen does not look like Figure T1.2, check the input and try again. If the job is still failing after the third attempt, please write to support at docking.org for assistance.
  • P2.3. Read what is reported by the Scrutinizer (Figure T1.2), and proceed to the Job Watcher by clicking on the link at the bottom of the page when you are ready.
  • P2.4. You should now be in the Job Watcher (Figure T1.3). Depending on how much time has elapsed, and how busy our cluster is, you will see a progress report of the current status of your job. As time passes, the yellow status indicator should progress from left to right indicating the progress of your job through Target Preparation and Calibration.
    Figure T1.3
  • P2.5. If all goes as usual, your job will have completed within an hour. You may reload the Job Watcher at any time to get an updated status report of your job. When calibration is complete, you may review the preliminary results and decide on the next course of action.
  • P2.6 Review Calibration results. blah blah blah.
Figure T1.4


Proposed Research

Preliminary results above show that docking is able to enrich known actives from among a database of decoys. This suggests that prospective docking for discovery of novel ligands is reasonable and can be expected to suggest interesting compounds to test.

Protocol P3. Dock the "fragment-like" purchasable compounds from ZINC

Protocol P4. Review and interpret fragment docking results

Protocol P5. Follow up calculations and variations

Possible problems and alternative approaches

Literature Cited

We refer you to our publications pages for theory and practice of docking and virtual screening.

Document status: working tutorial. Please correct any errors you may find.