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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