1 HPC in Dr HPC in Drug ug Disco Discover ery Ashutosh - - PowerPoint PPT Presentation

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Chemistry Lab based

• Expensive
• Protracted
• Difficult

HPC MD-based Simulations

• Inexpensive
• Very fast
• Useful for early stages

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Technologies in Drug Discovery

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

Absorption Distribution Metabolism Excretion Toxicity Chemical database N=1,000,000 Lead candidates N=500 Affinity Selectivity Activity Drug-like?

Structure-based & Ligand-based screens

Inactive

Computational Tools:

• DESMOND
• GROMACS
• CHARMM
• SCHRODINGER

. . .

HPC in Drug Discovery 3

In silico Screening Complements High-throughput Screening

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

HPC in Drug Discovery 4

Drug Discovery

Drug Discovery: Driven by Computation and Experiments

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

Cell membrane

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• Important in Lipid-mediated cell signaling and metabolism.
• Derangement in Signaling: Neurodegenerative diseases and many forms of

cancers.

Phosphatidylinositol Transfer Proteins (PITPs) Important in Cell Function

Drug PI/PC Lipid Signaling molecule Lipid exchange at binding cavity Membrane docking. Dynamic Gate Drug binding to Sec14-PITP cavity

• 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

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Phosphatidylinositol Transfer Proteins (PITPs) Critical in Cell Function

Sec14-OPEN

‘Transition state’?

CLOSED

Gate

Schaaf et. al. Mol. Cell. (2008)

Sec14-OPEN Sfh1-CLOSED (Sec14 homolog)

Identity: 62 % Similarity: 78 % Homology: 77 % Yellow: Sfh1 Blue: Sec14-OPEN Red: Sec14 Homology Model-CLOSED

• Sec14 is a PITP protein;
• It’s binding to the PI and PC lipids is

studied using the SCHRODINGER & DESMOND MD codes

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Homology Modeling of Sec14 (Closed Conformation)

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

~106 – 109 molecules

SCORING & RANKING

VALIDATED DOCKING MODELS

INACTIVES HITS (confirmed actives) CHEMICAL DATABASE

Decoys: known or presumed non-binders to the target protein.

Ligands + decoys Target Structure

Docking

High Score

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Docking-Based Virtual Screening

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Sec14 Homology Model: All-Atom MD Simulation

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

HPC in Drug Discovery 10

Simulation of Drug Binding to Protein Using DESMOND MD Code

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

HPC in Drug Discovery 11

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

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Small molecule (drug) vibrating in Sec14 binding pocket (Used DESMOND MD Code)

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

HPC in Drug Discovery 13

Conclusion

HPC HPC in Dr in Drug ug Disco Discover ery

Ashutosh Tripathi, Ph.D. Bankaitis Lab Department of Molecular and Cellular Medicine, TAMHSC

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.

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