1 Technologies in Drug Discovery Chemistry Lab based HPC MD-based - PowerPoint PPT Presentation

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Technologies in Drug Discovery Chemistry Lab based HPC MD-based Simulations • Expensive • Inexpensive • Protracted • Very fast • Difficult • Useful for early stages HPC in Drug Discovery 2

In silico Screening Complements High-throughput Screening Structure-based & Ligand-based screens Chemical database N=1,000,000 Absorption Distribution Affinity Metabolism Selectivity Drug-like? Excretion Activity Toxicity Computational Tools: • DESMOND • GROMACS • CHARMM Lead candidates Inactive N=500 • SCHRODINGER . . . HPC in Drug Discovery 3

Drug Discovery: Driven by Computation and Experiments Drug Discovery HPC in Drug Discovery 4

Phosphatidylinositol Transfer Proteins (PITPs) Important in Cell Function  Important in Lipid-mediated cell signaling and metabolism.  Derangement in Signaling: Neurodegenerative diseases and many forms of cancers. Lipid exchange at binding cavity Drug Membrane docking. PI/PC Lipid Drug binding to Dynamic Gate Signaling molecule Sec14-PITP cavity Cell membrane 5 HPC in Drug Discovery

Phosphatidylinositol Transfer Proteins (PITPs) Critical in Cell Function • Important in Lipid-mediated cell signaling and metabolism. • Derangement in Signaling: Neurodegenerative diseases and many forms of cancers. • Undergoes Conformational Changes: Helical Gate Mediates Lipid Access/Exchange Gate Sec14-OPEN CLOSED HPC in Drug Discovery ‘Transition state’? 6 Schaaf et. al. Mol. Cell. (2008)

Homology Modeling of Sec14 (Closed Conformation) • Sec14 is a PITP protein; • It’s binding to the PI and PC lipids is studied using the SCHRODINGER & DESMOND MD codes Sec14-OPEN Sfh1-CLOSED (Sec14 homolog) Yellow: Sfh1 Blue: Sec14-OPEN Identity: 62 % Red: Sec14 Homology Model-CLOSED Similarity: 78 % Homology: 77 % HPC in Drug Discovery 7

Docking-Based Virtual Screening VALIDATED SCORING & DOCKING RANKING MODELS Ligands + decoys Target Structure Docking High HITS (confirmed Score actives) ~10 6 – 10 9 molecules CHEMICAL DATABASE INACTIVES Decoys: known or presumed non-binders to the target protein. 8 HPC in Drug Discovery

Sec14 Homology Model: All-Atom MD Simulation HPC in Drug Discovery 9

Simulation of Drug Binding to Protein Using DESMOND MD Code HPC in Drug Discovery 10

All-Atom Simulation of Sec14 in Explicit Water Molecules (used DESMOND MD Code) HPC in Drug Discovery 11

Small molecule (drug) vibrating in Sec14 binding pocket (Used DESMOND MD Code) HPC in Drug Discovery 12

Conclusion HPC in Drug Discovery 13

Ashutosh Tripathi, Ph.D.  Ph.D. (Pharmaceutical Sciences), Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, U.S.A.  Master of Science in Cheminformatics, Department of Chemistry, University of Manchester, U.K.  Bachelor of Pharmacy, Institute of Engineering and Technology, M.J.P. Rohilkhand University, India. Research Interest  Computer-aided drug design.  Algorithm and software development for designing new drugs.  Cancer therapeutics.  Clinical informatics.  ADME/Tox QSAR modeling. 14 HPC in Drug Discovery