title: Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2).
abstract: Molecular models of the complex between the selective COX-2 inhibitor nimesulide and the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 have been built using a combination of homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and interaction energy decomposition. It is found that nimesulide exploits the extra space made available by the replacement at position 523 of an isoleucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 numbering). Two alternate binding modes are proposed which are compatible with the pharmacological profile of this agent as a COX-2 selective inhibitor.
authors.affiliation: Departamento de Farmacología, Universidad de Alcalá, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: García-Nieto
authors.forename: C
authors.initials: C
authors.lastname: Pérez
authors.forename: F
authors.initials: F
authors.lastname: Gago
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; 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; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide