title: Modeling cyclooxygenase inhibition. Implication of active site hydration on the selectivity of ketoprofen analogues.
abstract: Molecular modeling studies performed on the two cyclooxygenase isozymes (COXs) suggest that active site hydration is crucial for understanding inhibitor selectivity. In this work, models have been constructed considering some implicit water molecules, placed in the position suggested by GRID, that participate in the dynamic hydrogen-bonding network at the polar active site entrance together with protein residues 355, 524, 120, and 513. The selectivity observed for ketoprofen (1) and the structural analogues 2 and 3 may be rationalized in terms of such implicit hydration.
authors.affiliation: R & D Department, Laboratorios Menarini, Alfonso XII 587, 08918 Badalona, Spain. apalomer@menarini.es
authors.forename: A
authors.initials: A
authors.lastname: Palomer
authors.forename: J J
authors.initials: JJ
authors.lastname: Pérez
authors.forename: S
authors.initials: S
authors.lastname: Navea
authors.forename: O
authors.initials: O
authors.lastname: Llorens
authors.forename: J
authors.initials: J
authors.lastname: Pascual
authors.forename: L
authors.initials: L
authors.lastname: García
authors.forename: D
authors.initials: D
authors.lastname: Mauleón
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D014867:Water / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D014867:Water; D007660:Ketoprofen; D011451:Prostaglandin-Endoperoxide Synthases