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

▶
1 technologies in drug discovery
SMART_READER_LITE
LIVE PREVIEW

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

Jun 09, 2023 111 likes •252 views

1 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

slide-1
SLIDE 1

1

slide-2
SLIDE 2

Chemistry Lab based

  • Expensive
  • Protracted
  • Difficult

HPC MD-based Simulations

  • Inexpensive
  • Very fast
  • Useful for early stages

HPC in Drug Discovery 2

Technologies in Drug Discovery

slide-3
SLIDE 3

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

slide-4
SLIDE 4

HPC in Drug Discovery 4

Drug Discovery

Drug Discovery: Driven by Computation and Experiments

slide-5
SLIDE 5

Cell membrane

HPC in Drug Discovery 5

  • 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

slide-6
SLIDE 6
  • 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

HPC in Drug Discovery 6

Phosphatidylinositol Transfer Proteins (PITPs) Critical in Cell Function

Sec14-OPEN

‘Transition state’?

CLOSED

Gate

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

slide-7
SLIDE 7

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

HPC in Drug Discovery 7

Homology Modeling of Sec14 (Closed Conformation)

slide-8
SLIDE 8

~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

HPC in Drug Discovery 8

Docking-Based Virtual Screening

slide-9
SLIDE 9

HPC in Drug Discovery 9

Sec14 Homology Model: All-Atom MD Simulation

slide-10
SLIDE 10

HPC in Drug Discovery 10

Simulation of Drug Binding to Protein Using DESMOND MD Code

slide-11
SLIDE 11

HPC in Drug Discovery 11

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

slide-12
SLIDE 12

HPC in Drug Discovery 12

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

slide-13
SLIDE 13

HPC in Drug Discovery 13

Conclusion

slide-14
SLIDE 14

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.

HPC in Drug Discovery 14