CoMFA and CoMSIA analyses of highly selective pipecolic acid based TNF-α converting enzyme (TACE) inhibitors using docked conformations for molecular alignment

Molecular modeling (MM) study is performed for Pipecolic acid based derivatives (PSAs) of tumor necrosis factor-α converting enzyme (TACE) inhibitors because of their very high selectivity for TACE over MMP-1. MM study was carried out by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular field Similarity Indices Analysis (CoMSIA) approaches. Computational docking simulations have also been performed to explore atomic details of TACE/PSA interactions and to identify the most important structural features of PSAs vital for TACE inhibitory activity. Molecular modeling study was performed using probable bioactive conformations, generated employing docking, for molecular alignment. The CoMSIA model resulted to be more predictive than CoMFA model, and gave conventional r2 0.996, r² cv 0.765, q2 0.783, SEE 0.025, F-value 472.149, r² boot 0.999 and r² test 0.788. Generated 3D-QSAR field contributions (contour maps) and results of docking analysis showed good correlation. Therefore, present studies will be useful for designing new molecules with improved TACE inhibitory activity in future.