Three‐dimensional Quantitative Structure‐Activity Relationship Analyses of a Series of Butenolide ETA Antagonists

Abstract

AbstractTwo kinds of Three‐dimensional Quantitative Structure‐activity Relationship (3D‐QSAR) methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied to analyze the structure‐activity relationship of a series of 63 butenolide ETA selective antagonists with respect to their inhibition against human ETA receptor. The CoMFA and CoMSIA models were developed for the conceivable alignment of the molecules based on a template structure from the crystallized data. The statistical results from the initial orientation of the aligned molecules show that the 3D‐QSAR model from CoMFA (q2 = 0.543) is obviously superior to that from the conventional CoMSIA (q2 = 0.407). In order to refine the model, all‐space search (ASS) was applied to minimize the field sampling process. By rotating and translating the molecular aggregate within the grid systematically, all the possible samplings of the molecular fields were tested and subsequently the one with the highest q2 was picked out. The comparison of the sensitivity of CoMFA and CoMSIA to different space orientation shows that the CoMFA q2 values are more sensitive to the translations and rotations of the aligned molecules with respect to the lattice than those of CoMSIA. The best CoMFA model from ASS was further refined by the region focused technique. The high quality of the best model is indicated by the high cross‐validated correlation and the prediction on the external test set. The CoMFA coefficient contour plots identify several key features that explain the wide range of activities, which may help us to design new effective ETA selective antagonists.