|
|
| (8 intermediate revisions by 3 users not shown) |
| Line 1: |
Line 1: |
| '''DOCK Blaster Tutorial 1. Dock to Mineralocorticoid receptor''' A[[DOCK Blaster:Tutorials | DOCK Blaster Tutorial]]. | | '''DOCK Blaster Tutorial 1. Dock to Human Thyroid Hormone Receptor Beta-1 (TR beta)''' |
|
| |
|
| [[Image:2aa2.jpg|thumb|right|Mineralocorticoid receptor, PDB 2aa2]] | | A[[DOCK Blaster:Tutorials | DOCK Blaster Tutorial]]. |
|
| |
|
| = Specific Aims =
| |
| This tutorial will show you how to retrospectively dock a crystallographically observed ligand, aldosterone, into the human mineralocorticoid receptor, PDB code
| |
| [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2AA2 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?
| | ==Step 1== |
| * 2. Can DOCK Blaster enrich known actives from a database of property-matched decoys?
| | a. Browse to the DOCK Blaster main page: |
| * 3. Can DOCK Blaster suggest novel, commercially available ligands for MR?
| | http://blaster.docking.org/ |
| | and select '''Start with a PDB code''' from the '''DOCK''' pull down menu: |
| | http://blaster.docking.org/parser.shtml |
| | b. In the PDB code field, enter 1N46, the PDB code for TR beta. |
| | http://www.ebi.ac.uk/msd-srv/oca/oca-bin/ocashort?id=1N46 |
| | Click on '''DOCK''' to start. |
|
| |
|
| [[Image:Aldosterone.png|thumb|right|Aldostereone, the crystallographically observed ligand of MR in PDB 2aa2]]
| |
|
| |
|
| {{TOCright}}
| | If you are really impatient you can do all of the above |
| | by simply clicking here: |
| | http://blaster.docking.org/cgi-bin/parser.pl?code=1N46 |
|
| |
|
| = Background and Significance = | | ==Step 2== |
| 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. [http://en.wikipedia.org/wiki/Mineralocorticoid_receptor see Wikipedia].
| | You will get a confirmation page showing that the target has been looked up correctly at the PDB. To proceed, click on "DOCK". Write down the DOCK Blaster Job ID number. You will need it. The docking process is now queued, and may have started if the system is not overloaded. |
| | [[File:DOCK_Blaster_step1a.png|300px|center]] |
|
| |
|
| 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.
| | ==Step 3== |
| | Click on the link to browse progress at the bottom of the page |
| | http://blaster.docking.org/cgi-bin/jobwatch.pl?job_id=35605&pin= |
| | (replace the job number with your actual job number. This one will not work) |
|
| |
|
| = 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 [[DOCK Blaster:Input Preparation | Input Preparation]] for details.
| |
|
| |
|
| == Protocol P1 - Acquire target structure and prepare input files ==
| | Step 4. When the job has finished, you will be in the "Calibration Done" state as shown in the progress bar with the yellow paint near the top of the page. You will see a report that reports how well docking worked. |
| * 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]]).
| |
|
| |
|
| [[Image:DBtut1_1f.jpg|thumb|right|Figure T1.1 - Prepare input and launch job]]
| | Step 5. Interpreting the calibration summary table |
|
| |
|
| == 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.
| |
| ** 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).
| | Step 6. Inspecting further details and poses of the ligand and decoys. |
| [[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.
| | Step 7. Launching a docking job |
|
| |
|
| * 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]]
| |
|
| |
|
| * 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.
| |
|
| |
| [[Image:DBtut1_4f.jpg|thumb|right|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 = | | = Literature Cited = |
| We refer you to our publications pages for theory and practice of docking and virtual screening. | | 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. | | Document status: working tutorial. Please correct any errors you may find. |
|
| |
|
| [[Category:DOCK Blaster]] | | [[Category:DOCK Blaster]] |
| [[Category:Tutorials]] | | [[Category:Tutorials]] |
DOCK Blaster Tutorial 1. Dock to Human Thyroid Hormone Receptor Beta-1 (TR beta)
A DOCK Blaster Tutorial.
Step 1
a. Browse to the DOCK Blaster main page:
http://blaster.docking.org/
and select Start with a PDB code from the DOCK pull down menu:
http://blaster.docking.org/parser.shtml
b. In the PDB code field, enter 1N46, the PDB code for TR beta.
http://www.ebi.ac.uk/msd-srv/oca/oca-bin/ocashort?id=1N46
Click on DOCK to start.
If you are really impatient you can do all of the above
by simply clicking here:
http://blaster.docking.org/cgi-bin/parser.pl?code=1N46
Step 2
You will get a confirmation page showing that the target has been looked up correctly at the PDB. To proceed, click on "DOCK". Write down the DOCK Blaster Job ID number. You will need it. The docking process is now queued, and may have started if the system is not overloaded.
Step 3
Click on the link to browse progress at the bottom of the page
http://blaster.docking.org/cgi-bin/jobwatch.pl?job_id=35605&pin=
(replace the job number with your actual job number. This one will not work)
Step 4. When the job has finished, you will be in the "Calibration Done" state as shown in the progress bar with the yellow paint near the top of the page. You will see a report that reports how well docking worked.
Step 5. Interpreting the calibration summary table
Step 6. Inspecting further details and poses of the ligand and decoys.
Step 7. Launching a docking job
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.
