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Docking and Virtual Screening
Using the BMI cluster
Jacek Biesiada
Cincinnati, 2008
The Docking Problem
Finding the geometry and strength of ligand binding to a receptor.
High Throuput Docking
and Virtual Screening for Drug Design
• Definition of Virtual Screening
Use of high-performance computing to analyze large
database of chemical compounds in order to indetify
possible drug candidates.
W.P. Walters, M.T. Stahl and M.A. Murcko, „Virtual Screening-An Overview”, Drug Discovery Today, 3,
160-178 (1998)
• Virtual Screening is also known as:
• High-Throughput Docking
• High-Throughput Virtual Screening
Why Use Virtual Screening ?
• VS is a computational filter:
– Reduces the size of a chemical library to be screened experimentaly ~ 106
to 103 – Saves time & money
– ZINC library version 2007, only „drug-like” compounds ~ 2.2 * 106
Expected ZINC version 2008 about 4 * 106 compounds
• May improve likelihood of finding interesting compounds
–
–
As oppoesed to random screening
Enhance „hit rates”
• VS can:
–
Evaluate virtual combinatorial libraries before synthesized
• VS can be usefull tool for discovering new targets
in „post-genomic” era
Examples of aplications: Design of inhibitors for Norovirus and
Glycoprotein IV
(collaboration with Jason Jiang, CCHMC and
Andrew B. Herr – UC College of Medicine )
Autodock
• AutoDock has been widely-used and there are many
examples of its successful application in the literature:
(First clinicaly-approved HIV Integrase Inhibitor – Autodock
used during the research – prof. Andrew McCammon)
• Citation Index showed more than 1100 publications have
cited the primary AutoDock methods papers.
• It is very fast, provides high quality predictions of ligand
conformations, and good correlations between predicted
inhibition constants and experimental ones.
• Very well calibrated force fieled (188 known protein)
• Autodock is free software and version 4 is distributed
under the GNU General Public License
Screening Pipeline: Scripts to
Run Autodock on BMI Cluster
• Adscr.pl – input: Receptor.cfg adscr.cfg Ligand_info[1-N_CPU]
– output:
*_ki, *_cl. *_bestlig, *_currentlig, *_errors
• Que.pl - input: Number_of_CPU Receptor.cfg Ligand_info_all
• Best.pl - input: File with results (*_ki)
• Restart.pl – building new Ligand_info_all file in case of restart of
calculation
Ligand_info_all (Ligand_info) – example:
862418 862450 ZINC00041309 3_p0.0.pdbqt
2 862453 862484 ZINC00041344 3_p0.0.pdbqt
3 862487 862528 ZINC00041448 3_p0.0.pdbqt
...................... 2200000 line ................................
Preparing Receptor and Ligand for
Docking Simulations
• Prepare_receptor.pl – input: Receptor.pdb 3(4)
• Prepare_gpf.pl - – input: Receptor.pdb Ligand.pdb 3(4)
binding site, grid box
• Autogrid.pl – input: Receptor.pdb Ligand.pdb 3(4)
• Configure: Receptor.cfg
adscr.cfg
- Read the „Tutorial” connected to prepared scripts
– all details connected with Virtual Screening
Our Library of Compounds
• Library in directory
• ZINC offer four formats:
– sdf, mol2, Smail and flexibase
/database/Zinc/
/mol2
/sdf
/pdb
/pdbq
/pdbqt
(version from 2007)
/sdf_index
/pdb_index
/pdbq_index (Autodock v.3)
/pdbqt_index (Autodock v.4)
Virtual Screening is CPU
Intensive: Some Estimates
Using BMI Cluster
• 2.2 mln compounds
• On average 1 min for one docking
(depends of grid map and several search
parameter – with default value)
• 50 CPU
• ((2200000/50)/ 60min)/ 24h ~ 30 day
• About 30 days – 1th screeaning
Validation and Analysis of
Docking Results
• Similarity compounds
molprint2d – http://www.molprint.com (free)
Method based on MOLecular fingerPRINT
• ADME (absorption, distribution, metabolism, excretation)
Paramaters like: Molecular weight, LogP, LogD, pKa , number of
H-bond donor/acceptor, PSA, ,... (15-16 parameters)
ALOGS – http://www.vcclab.org/lab/alogps (free)
JChem (MARVIN, JCLUSTOR)
– http://www.chemaxon.com/ (free for academic research)
Future Work
•
•
•
•
•
Testing scripts
Increase library of compounds
Writing good „Tutorial” for users
Gold standard – similarity and ADME ?
Improve scripts for finall-automatic
analisys of docking, similarity and ADME.
»THANK YOU