title: Quantitative structure-activity relationships for commercially available inhibitors of COX-2.
abstract: Quantitative structure activity relationship (QSAR) studies of selective COX-2 inhibitors of commercial interest (drugs in market and on clinical trials) were performed. The COX-2 inhibitory activity (pIC(50)=-logIC(50)) of these twelve compounds was correlated with nineteen descriptors including steric, electronic and constitutional parameters. pIC(50) activity showed high positive correlation with both volume and HOMO (Highest occupied molecular orbital). A Biparametric model was developed that included both these descriptors. The predictive capability (q(2)= 0.66) of this equation was satisfactory. So it can be used to design newer templates or modify existing templates. Volume is an important parameter for the selective COX-2 inhibitory activity, because the secondary pocket in the active site of this enzyme is bigger than the active site of COX-1 enzyme (by 17%). HOMO is a measure of the nucleophilicity of the molecule and a molecule with high HOMO energy is ready to donate its electrons and thus is more reactive than molecule with low values. Binding studies were performed between the COX-2 enzyme and these molecules. The inhibitory activity increased with decrease in binding energy (or interaction energy) between the compounds with the COX-2 enzyme (with a correlation coefficient = -0.65). Calculated Log BBB (Blood Brain barrier), Log P (octonol water partition) and HBD (hydrogen bond donor) values were in the acceptable range (i.e., BBB = -1 to 0.3; LogP= 0 to 5; HBD < 5).
authors.affiliation: Department of Biotechnology, Indian Institute of Technology, Madras, Chennai - 600 036, India.
authors.forename: P M
authors.initials: PM
authors.lastname: Sivakumar
authors.forename: M
authors.initials: M
authors.lastname: Doble
mesh_terms: D001665:Binding Sites; D001812:Blood-Brain Barrier; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2