Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

Abstract As a basis for predicting structural features that may lead to the design of more potent and selective inhibitors of choline acetyltransferase (ChAT), the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of trans -1-methyl-4-(1-naphthylvinyl)pyridinium (MNVP + ) analogs, which are known ChAT inhibitors. 3D-QSAR studies were carried out using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Since these inhibitors have extremely shallow potential energy minimum energy wells and low barriers to rotation, two dihedral angles unique to these inhibitors were systematically modified to reflect the energetically preferred conformations as determined by force field calculations. An optimum alignment rule was devised based on the conformations obtained from the molecular mechanics studies, using a common substructure alignment method. The studies involve a set of 21 compounds and experimentally determined molar IC 50 values were used as the dependent variable in the analysis. The 3D-QSAR models have conventional r 2 -values of 0.953 and 0.954 for CoMFA and CoMSIA, respectively; similarly, cross-validated coefficient q 2 -values of 0.755 and 0.834 for CoMFA and CoMSIA, respectively, were obtained. On the basis of these predictive r 2 -values the model was tested using previously determined IC 50 values. CoMSIA 3D-QSAR yielded better results than CoMFA.