CoMFA, CoMSIA and GRID/GOLPE studies on calcium entry blocking 1,4-dihydropyridines

Three different 3D QSAR methods have been applied for a common pharmacophore model of 45 calcium antagonistically active 1,4-dihydropyridines (DHP) in order to find best correlation of interaction fields and biological activity. Analysis for the entire data set yielded r2/q values in a range starting from 0.821/0.620 (GRID/GOLPE) over 0.872/0.600 (CoMFA) to 0.908/0.744 (CoMSIA). The robustness of these models was tested not only via leave-one-out but also by leave-9-out crossvalidations. Furthermore, models were constructed using a subset of 37 DHPs (training set) allowing the prediction of activity for the residual 8 DHPs (test set). The training set yielded r2/q values starting from 0.826/0.672 (GRID/GOLPE) over 0.872/0.540 (CoMFA) to 0.899/0.662 (CoMSIA). For the test set r values from 0.677 (GRID/GOLPE) over 0.639 (CoMFA) to 0.470 (CoMSIA) were calculated. Besides the statistics, each 3D QSAR model yields further information by analysis of the generated contour maps. Consideration of the CoMFA and CoMSIA fields indicates unfavourable steric interactions for bulky moieties in 4′-position. On the other hand, sterical demanding 2′- and 3′-substituents are favourable and the biological activity of DHPs is further increased if these moieties produce a negative electrostatic potential. In contrast, high π-electron density on top of and parallel to the 4-phenyl ring beside the 2′-position is associated with decreasing activity. This could point to repulsive electronic interactions with binding site residues or to the potential of electron-deficient 4-aryl moieties to behave as electron acceptors in a charge transfer (CT) mechanism.