Diltiazem-like calcium entry blockers: A hypothesis of the receptor-binding site based on a comparative molecular field analysis model

A series of 26 pyrrolo[2,1-c][1,4]benzothiazines, which have been already synthesized and reported to show calcium antagonist activity in both radioligand-binding assays and functional studies, were investigated using the comparative molecular field analysis (CoMFA) paradigm. Due to the lack of experimental structural data on these derivatives, the minimum energy conformers obtained by molecular mechanics calculations were used in the subsequent study. Structures were aligned following an alignment criterion based on the pharmacophoric groups of the studied compounds. The predictive ability of the CoMFA model was evaluated using a test set consisting of three representative compounds. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r(2) values equal to 0.703, 0.970, and 0.865, respectively, the average absolute error of predictions being 0.26 log unit. The predictive capability of this model was also tested on a further test set of molecules consisting of diltiazem and nine pyrrolo[2,1-d][1,5]benzothiazepines endowed with calcium antagonist activity. The accurate results obtained also in this case revealed the robustness of the model. On the basis of the same alignment, the structural moieties of the studied calcium entry blockers which are thought to contribute to the biological activity were identified, and a possible receptor-binding site for all these compounds is presented taking into account the information derived from the analysis of the steric and electrostatic CoMFA contour maps.