CADD Center 2009 update Identify Target: Biological and Structural Data Virtual Database Screening (Docking) from 1M to 100 cmpds 10 4 enhancement Biological Assay Lead Compounds Lead Optimization Drug Candidate Compound selection for assay Dissimilarity and physico-chemical properties Pharmacokinetics Toxicology etc.
Virtual commercially available scompound database 1 million compounds for 3D docking studies 5.4 million compounds for similarity searching Updated annually
Methodological developments for lead compound optimization CADD based lead optimization requires accurate mathematical modeling of a large number of chemical entities: Challenge for computational chemistry! CHARMM general force field ( CgenFF ): Force field for pharmaceutical compounds compatible with the highly optimized CHARMM biomolecular force fields.
Methodological developments for Lead compound optimization <ul><li>SILCS: Site Identification by Ligand Competitive Saturation </li></ul><ul><li>Computational approach to fragment based drug design </li></ul><ul><li>“ Rigorous” free energy evaluation of relative ligand affinity </li></ul><ul><ul><li>Protein flexibility Explicit solvent representation </li></ul></ul><ul><li>Allow multiple ligands to compete for sites on the entire protein surface in explicit solvent MD simulations </li></ul>