MAPPING OF THE BENZOTHIAZEPINE BINDING-SITE ON THE CALCIUM-CHANNEL

A new pharmacophoric model of the benzothiazepine (diltiazem) binding site on the L-type Ca2+ channel was derived by using the SYBYL softwar e package. The molecular modeling study was conducted by applying the active analogue approach in a two-step procedure. In the first stage, the bioactive conformation of (+)cis-diltiazem, used as a reference te mplate, was found by including the most rigid and active derivatives i nto a preliminary MULTIFIT procedure. In the second step, aimed at map ping of the binding site, the common low-energy conformations of activ e and inactive analogues from various chemical classes were superimpos ed on the diltiazem template. It was hypothesized that the essential p harmacophoric elements are two aromatic rings and a protonated amine n itrogen. This pharmacophore hypothesis was later supported by several lines of evidence. All molecular superimpositions were performed by us ing a flexible fit on five dummy points built on the essential pharmac ophore. Molecular mechanics and dynamics were used to determine the lo west energy conformations of all the compounds as well as the conforma tions that displayed the common pharmacophoric geometry. Based on the van der Waals volume manipulations of the active and inactive analogue s, a three-dimensional model estimating the binding site topography wa s derived; various regions on the boundary of the binding domain were characterized and discussed, along with other factors, in terms of pot ential improvement of the drug binding affinity.