title: Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis.
abstract: The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2, BP 83, F-59006 Lille Cédex, France. pchavatt@phare.univ-lille2.fr
authors.forename: P
authors.initials: P
authors.lastname: Chavatte
authors.forename: S
authors.initials: S
authors.lastname: Yous
authors.forename: C
authors.initials: C
authors.lastname: Marot
authors.forename: N
authors.initials: N
authors.lastname: Baurin
authors.forename: D
authors.initials: D
authors.lastname: Lesieur
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry; D001665:Binding Sites; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D003517:Cyclopentanes / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry*; D007555:Isoxazoles / Q000737:chemistry; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry
chemical_list: D001555:Benzene Derivatives; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003517:Cyclopentanes; D007093:Imidazoles; D007527:Isoenzymes; D007555:Isoxazoles; D011720:Pyrazoles; D011758:Pyrroles; D013141:Spiro Compounds; D013876:Thiophenes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases