Molecular modeling study of diltiazem mimics at L-type calcium channels.

Abstract

A theoretical study was performed to generate a pharmacophore model for chemically diverse structures that specifically interact with the diltiazem binding site of L-type calcium channels. Via molecular mechanics and quantum chemical methods solvation energies, logP values, conformational and electronic features of classical 1,5-benzothiazepin-4(5H)-one (BTZ, e.g., diltiazem), 1-benzazepin-2-one (BZ), pyrrolo[2,1-d][1,5]benzothiazepine, pyrrolo[2,1-c][1,4]benzothiazine, and benzobicyclo[2.2.2]octyl amines derivatives were determined. Furthermore, the molecular electrostatic potentials (MEPs) and common interaction fields derived from use of the GRID programme were compared. This yielded a pharmacophore model with three crucial pharmacophoric characteristics, (1) two aromatic ring systems in a distance of about 6.7 A, (2) a basic side chain with pKa in the physiological range, and (3) a 4'-methoxy moiety. In addition, a strong negative MEP in 4-position (carbonyl oxygen) and hydrophobic electron-rich features in the position equivalent to the sulphur atom of BTZ derivatives were explored to be favourable for receptor binding and calcium antagonistic effect. Moreover, the stabilizing effect of substituents in 3-position of BZs on the bioactive "M" twist-boat conformation of the heptagonal ring could be demonstrated by molecular dynamics simulations. Based on these molecular descriptors, the quinazolinone derivative MCI-176 is predicted to be a potential ligand of the diltiazem binding site.