title: Molecular docking towards drug discovery.
abstract: Fueled by advances in molecular structure determination, tools for structure-based drug design are proliferating rapidly. Lead discovery through searching of ligand databases with molecular docking techniques represents an attractive alternative to high-throughout random screening. The size of commercial databases imposes severe computational constraints on molecular docking, compromising the level of calculational detail permitted for each putative ligand. We describe alternative philosophies for docking which effectively address this challenge. With respect to the dynamic aspects of molecular recognition, these strategies lie along a spectrum of models bounded by the Lock-and-Key and Induced-Fit theories for ligand binding. We explore the potential of a rigid model in exploiting species specificity and of a tolerant model in predicting absolute ligand binding affinity. Current molecular docking methods are limited primarily by their ability to rank docked complexes; we therefore place particular emphasis on this aspect of the problem throughout our validation of docking strategies.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Gschwend
authors.forename: A C
authors.initials: AC
authors.lastname: Good
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005544:Forecasting; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011010:Pneumocystis / Q000187:drug effects / Q000201:enzymology; D012984:Software; D013045:Species Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase