Three-dimensional quantitative structure–activity relationship CoMFA/CoMSIA on pyrrolidine-based tartrate diamides as TACE inhibitors

Abstract

A series of pyrrolidine-based tartrate diamides having selective tumor necrosis factor-α converting enzyme (TACE) inhibitory activity was selected for the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies. Total 76 compounds were selected by considering a high deviation in the biological activity and structural variations. The quality and predictive power of 3D-QSAR, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for the atom-based, centroid/atom-based, data-based alignments were performed. Various models were developed with the help of these alignments. The best model was developed with data-based alignment. The optimal predictive CoMFA model was obtained with cross-validated r2 = 0.53 with six component, non-cross-validated r2 = 0.94, standard error of estimates 0.23, F-value = 121.98 and optimal CoMSIA model was obtained with cross-validated r2 = 0.53 with five components, non-cross-validated r2 = 0.93, standard error of estimates = 0.24 and F-value = 138.83. These models also showed the best test set prediction with predictive r2 value of 0.65 and 0.73, respectively. Thus, on the basis of predictive power COMSIA model appeared to be the best one. The statistical parameters from these models indicate that the data are being well fitted and also have high predictive ability. Moreover, the resulting 3D-CoMFA/CoMSIA contour maps provide useful guidance for designing of highly active TACE inhibitors.