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CADD and Molecular Modeling : Importance in Pharmaceutical Development. Dr. Sanjeev Kumar Singh Department of Bioinformatics Alagappa University e-mail- firstname.lastname@example.org. Working at the Intersection. Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology
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Dr. Sanjeev Kumar Singh
Department of Bioinformatics
Find a drug effective
against disease protein
disease (2-5 years)
Human clinical trials
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and “personalized” targets
HIGH THROUGHPUT SCREENING
Screening up to 100,000 compounds a
day for activity against a target protein
Using a computer to
Rapidly producing vast numbers
Computer graphics & models help improve activity
IN VITRO & IN SILICO ADME MODELS
Tissue and computer models begin to replace animal testing
Gene sequence data
Ligand binding data
Automating the CADD Process
de novo design
Phases of CADD
SAVING 12 – 15 years, Costs: 500 - 800 million US $
The pharmacophore model of HIV protease.
& potent drug
3'-azido thymidine (AZT)
2',3' dideoxy nucleoside
2',3'- didehydro dideoxy nucleoside
MESP contours for nucleosidic drugs. Red coloured contours indicate a value of -.01 for electrostatic potential and yellow contours indicate a value of -0.05
Threshold interaction energy of NRTI’s (nucleosidic inhibitors for Reverse transcriptase) to undergo competitive inhibition
2'3' dideoxy thymidine
AZT -16.71 kcal/mol
2'3'-didehydro 2'3'-dideoxy thymidine
Correlation of interaction energy with potency
Common binding mode for structurally and chemically diverse non- nucleosidic HIV-1RT inhibitors
Pyrrolyl hetro aryl sulfone with lysine
Arpita Yadav* and Sanjeev Kumar Singh, THEOCHEM, 723, 2005, 205-209.
CoMFA Steric Contours
Determine Protein Structure
Identify Interaction Sites
Discovery or design of molecules that interact with biochemical targets of known 3D structure
De Novo Design
X-ray structure of complex
Ligand docked into protein’s active site