title: Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis, comparative molecular similarity indices analysis, and docking studies of some 1,2-diarylimidazole derivatives.
abstract: Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on 114 analogues of 1,2-diarylimidazole to optimize their cyclooxygenase-2 (COX-2) selective antiinflammatory activities. These studies produced models with high correlation coefficients and good predictive abilities. Docking studies were also carried out wherein these analogues were docked into the active sites of both COX-1 and COX-2 to analyze the receptor ligand interactions that confer selectivity for COX-2. The most active molecule in the series (53) adopts an orientation similar to that of SC-558 (4-[5-(4-bromophenyl)-3-trifluoromethyl-1H-1-pyrozolyl]-1-benzenesulfonamide) inside the COX-2 active site while the least active molecule (101) optimizes in a different orientation. In the active site, there are some strong hydrogen-bonding interactions observed between residues His90, Arg513, and Phe518 and the ligands. Additionally, a correlation of the quantitative structure-activity relationship data and the docking results is found to validate each other and suggests the importance of the binding step in overall drug action.
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad 500 046, India. desiraju@uohyd.ernet.in
authors.forename: G R
authors.initials: GR
authors.lastname: Desiraju
authors.forename: B
authors.initials: B
authors.lastname: Gopalakrishnan
authors.forename: R K R
authors.initials: RK
authors.lastname: Jetti
authors.forename: A
authors.initials: A
authors.lastname: Nagaraju
authors.forename: D
authors.initials: D
authors.lastname: Raveendra
authors.forename: J A R P
authors.initials: JA
authors.lastname: Sarma
authors.forename: M E
authors.initials: ME
authors.lastname: Sobhia
authors.forename: R
authors.initials: R
authors.lastname: Thilagavathi
mesh_terms: D001665:Binding Sites; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry*; D007527:Isoenzymes / Q000737:chemistry*; D008968:Molecular Conformation; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases