THE ROLE OF MOLECULAR PROPERTY PREDICTORS IN DRUG DISCOVERY Anu Sharma Sales Manager – San Francisco, CA
The jargon we hear and the jargon speak !!! What must we know and why? Lipinski’s Rule Hydrogen-Bond donor acceptor Virtual molecules Compound Libraries Screening Molecular Modeling Structure Tables Proteins Biological data R-Group decomposition Log P Sub-structure searching Main Scaffold Key reactants Fragmentation IC50 EC50 Oral Bioavailability Drug-Like properties Combinatorial libraries Custom synthesis Medicinal Chemistry department Library Design Metabolic pathway CADD Batch Mode Calculations Active compounds Metabolites AnalogingPharmacophore Binding Ligands Small Molecules Molecular properties Organic Synthesis SAR – QSAR tables Structure Activity Relationships Synthetically feasible molecules Reaction schemes LogD Polar Surface Area Patents Lead optimizationClustering of data Canonicalization Reterosynthetic analysis Millions of compounds And many more…….
From bench side to bed side, what does it take?
When the prospects talk, where do they come from?
Discovering Drugs – How does the magic happen? A. Types of Drugs – Small Molecules Proteins & antibodies B. Site of action – Receptor C. Mechanism – Drug + Receptor = [Complex] = Effect D. Interactions – i) Hydrophobic Hydrophilic Ionic Steric E. Lead Identification Stage – High Thruput Screening “Hit to Lead” F. Lead Optimization Stage – Structure Activity Relationships “SAR”
Drive the SAR forward !!! Who will do that? Active Compounds - Molecular Properties – “Drug-Like” promise Key parameters used – Physical Properties – Rule of 5 Lipinski’s cal Potency - Lipophilicity LogP Selectivity - Binding affinity – Measure of charge LogD/HBDA Solubility – Permeability – Oral Bioavailability TPSA Ionization pKa Blood brain barrier penetration LogP/LogD Computer Aided Drug Designing – CADD Virtual screening (FBDD, SBDD, MCS, Physicochemical properties ) Space & Freedom - Intellectual Property Patents
References For more details on this subject – "Organic Chemistry Of Drug Design & Drug Action" - by Richard B Silverman. "Medicinal Chemistry : Principles & Practice" - by King. Tutorial on Drug Discovery & Development – Jen Eckstein Posted on the forum – Sales Meeting 2010