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3D QSAR Studies On Novel Terphenyls For Selective Inhibition Of Cyclooxygenase-2 Enzyme

Author(s): R Sharma, S. C Chaturvedi

Classical non-steroidal antiinflammatory drugs being non selective cyclooxygenase (cyclooxygenase-1 and 2) inhibitors are associated with serious adverse effects while selective cyclooxygenase-2 inhibitors are gastro safer non steroidal antiinflammatory drugs, as it is now well established that antiinflammatory activity of non steroidal antiinfiammatory drugs is due to the inhibition of cyclooxygenase-2 enzyme. In view of that we have identified essential biophoric (pharmacophoric) features on novel terphenyls (terphenyl methyl sulphonamides and sulphones) by the molecular modeling studies using APEX-3D expert system for selective inhibition of cyclooxygenase-2 and cyclooxygenase-1 enzyme. In addition to that multiparameter 3 dimensional quantitative structure activity relationship equations have also been generated, described relationships of biological activities with biophoric centers, global property and secondary sites and results can be used for structure optimization of novel terphenyls for selective inhibition of cyclooxygenase-2 enzyme and also for lead generation. As results of this study corroborates with the active sites of cyclooxygenase-2 and cyclooxygenase-1 enzymes, validate this study. Among several biophoric models generated, two models (1 and 2) for inhibition of cyclooxygenase-2 enzyme and other two models (3 and 4), for inhibition of cyclooxygenase-1 enzyme with good statistical values were selected. The purpose of study was to optimize selectivity of novel terphenyls towards inhibition of cyclooxygenase-2 enzyme, in order to that we have predicted the activity of prediction set compounds and described perfect prediction in 80% of the cases, validate the robustness of biophoric models for selective inhibition of cyclooxygenase-2. Different biophoric features and secondary sites for inhibition of cyclooxygenase-2 and cyclooxygenase-1 enzyme give an opportunity to design potent and highly selective cyclooxygenase-2 inhibitors.