Quantitative Structure-Activity Relationships for Commercially Available Inhibitors of COX-2

M.      Doble; P.   M.   Sivakumar

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 (pIC50=-logIC50) of these twelve compounds was correlated with nineteen descriptors including steric, electronic and constitutional parameters. pIC50 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 (q2= 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).

Keywords: COX-2, QSAR, HOMO, binding energy

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