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

Abstract

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 r 2 /q 2 cv values in a range starting from 0.821/0.620 (GRID/ GOLPE) over 0.872/0.600 (CoMFA) to 0.908/0.744 (CoM-SIA). 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 r 2 / q 2 cv 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 2 pred 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 p-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.

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

“…In particular, a study by Schleifer and Tot [42] aimed to apply and compare different methods for 3D-QSAR, such as GRID/GOLPE, CoMFA and COMSIA. The analysis of the set of 4-phenyl-substituted 1,4-DHPs indicated unfavourable steric interactions for bulky moieties in the para-position of the phenyl ring and favourable interactions for bulky substituents in ortho-and meta-positions.…”

Application of ab initio theory to QSAR study of 1,4‐dihydropyridine‐based calcium channel blockers using GA‐MLR and PC‐GA‐ANN procedures

“…The basic chemical structure of these compounds is shown in Figure 1, and their biological activity is represented in Table 1. Earlier QSAR studies indicated that the biological activity of these compounds is controlled by the electronic, hydrophobic, and steric factors 41–49. To find a relation between calcium channel antagonist activity and the quantum chemical features of the chemicals, a wide set of quantum chemical descriptors were calculated by the ab initio method.…”

“…1). The biological activity of these compounds were previously reported by Cobrun et al41 This data set has been used by the others 45–49. In Table 1 the structural features and the biological activity of the DHP derivatives used in this study are represented.…”

“…Another type of DHP compounds, in which nifedipine is their prototype (Fig. 1), has been the aim of many SAR36–40 and QSAR studies 41–49. Cobrun and coworkers determined the biological activity (tonic contractile response of longitudinal muscle strips of guinea pig ileum) and performed a QSAR study with a set of 46 DHP derivatives with a substituted phenyl on the C‐4 position of the DHP ring 41.…”

Molecular modeling and QSAR analysis of some 4,5-dichloroimidazolyl-1,4-DHP-based calcium channel blockers

“…1), the prototype of which is nifedipine, have been the aim of many SAR [6][7][8][9][10] and QSAR studies [11][12][13][14][15][16][17][18][19]. QSAR models are mathematical equations relating chemical structure to their biological activity.…”