Comparative Molecular Field Analysis of Selective Cyclooxygenase‐2 (COX‐2) Inhibitors

Abstract

The 3D-QSAR approach has been used to obtain informations about the active conformation of selective cyclo-oxygenase-2 (COX-2) inhibitors. In this paper, we have compared different combinations of two fields (steric and electrostatic) in order to optimize the 3D-QSAR models of selective COX-2 inhibitors. Assuming that all the compounds interact at the same binding site at the enzyme level, DuP697 pharmacophoric conformation served as a template for the superimposition of 54 structurally heterogeneous COX-2 inhibitors constituting both the training and test sets used to perform a 3D-QSAR study via the CoMFA method. A statistically significant model was obtained with 38 compounds of the training set (n=38, q2=0,70, N=3, r2=0,93, s=0,38, F=156) with steric and electrostatic relative contributions of 40% and 60%, respectively. The predictive power of the proposed model was discerned by successfully testing the 16 compounds constituting the test set. The so obtained and validated model brings important structural insights to aid the design of novel anti-inflammatory drugs prior to their synthesis.