DESIGN OF POTENTIAL CYCLOOXYGENASE INHIBITORS USING PHARMACOPHORE OPTIMIZATION BY MOLECULAR MODELING STUDIES

Recently discovery of relation between cyclooxygenase–2 (COX–2) inhibition and prevention of growth of cansar cells is a major area for research in medicinal chemistry, as it is free from side effects which are genetically shown by developed anticancer agents. In an attempt to develop potent and nontoxic COX–2 inhibitors, we have optimized the 1,5- diaryl pyrazole pharmacophore by using molecular modeling studies. In this paper we present results of 2D and 3D QSAR studies of a series of 22 molecules containing 1,5- diaryl pyrazole pharmacophore as selective COX–2 inhibitors. The 3D QSAR studies were performed using two different methods, stepwise variable selection k–nearest neighbor molecular field analysis (SW kNN–MFA) and simulated annealing k–nearest neighbor molecular field analysis (SA kNN–MFA) methods. The 2D QSAR studies were performed using multiple regressions. 3D QSAR studies produced reasonably good predictive models with high cross–validated r2cv value of 0.732 and 0.783 and predicted r2 value of 0.882 and 0.794 values using the models SW kNN–MFA and SA kNN–MFA method, respectively, whereas the r2 & predicted r2 value in 2D QSAR studies was found to be 0.84914 & 0.9157, respectively. the 2D QSAR studies indicated contribution of different physicochemical descriptors and the result of 3D QSAR studies indicated the exact steric and electronic requirement in the ranges at various positions in the 1,5- diaryl pyrazole pharmacophore. The pharmacophore requirement for selective COX–2 inhibition was optimized and requirement at various positions around 1, 5- diaryl pyrazole pharmacophore were defined.