title: Computational studies of COX-2 inhibitors: 3D-QSAR and docking.
abstract: The 3D-QSAR (three-dimensional quantitative structure-activity relationships) studies for 88 selective COX-2 (cyclooxygenase-2) inhibitors belonging to three chemical classes (triaryl rings, diaryl cycloalkanopyrazoles, and diphenyl hydrazides) were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Partial least squares analysis produced statistically significant models with q(2) values of 0.84 and 0.79 for CoMFA and CoMSIA, respectively. The binding energies calculated from flexible docking were correlated with inhibitory activities by the least-squares fit method. The three chemical classes of inhibitors showed reasonable internal predictability (r(2)=0.51, 0.49, and 0.54), but the sulfonyl-containing inhibitors demonstrated distinctively low binding energy compared to the others. The electrostatic interaction energy between the Arg513 of the COX-2 active site and sulfonyl group of the triaryl rings seemed to have the responsibility for difference in binding energy. Comparative binding energy (COMBINE) analyses gave q(2) values of 0.64, 0.63, and 0.50 for triaryl rings, diaryl cycloalkanopyrazoles, and diphenyl hydrazides, respectively. In this COMBINE model, some protein residues were highlighted as particularly important for inhibitory activity. The combination of ligand-based and structure-based models provided an improved understanding in the interaction between the three chemical classes and the COX-2.
authors.affiliation: Korea Research Institute of Chemical Technology, PO Box 107, Yusung-gu, Taejeon 305-343, South Korea.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Chong Hak
authors.initials: CH
authors.lastname: Chae
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Kyung-Lae
authors.initials: KL
authors.lastname: Park
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results
chemical_list: D016861:Cyclooxygenase Inhibitors