title: Rationale for the observed COX-2/COX-1 selectivity of celecoxib from Monte Carlo simulations.
abstract: Computational studies have yielded an analysis of the contributions to the free energy difference between the binding of celecoxib to COX-1 and to COX-2. The energetic and structural results point to the Ile to Val mutation at residue 523 as the key contributor to COX-2 selectivity; unfavorable steric contact between a sulfonamide oxygen and the delta methyl group of Ile523 destabilizes the complex with COX-1. The His to Arg change at residue 513 is less significant.
authors: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors: M L
authors: ML
authors: Price
authors: W L
authors: WL
authors: Jorgensen
mesh_terms: D019943:Amino Acid Substitution; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins; D008958:Models, Molecular; D009010:Monte Carlo Method; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib