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

• Published in: Pharmaceutical research Vol. 16; no. 10; pp. 1506 - 1513
• Main Authors: SCHLEIFER, K.-J, TOT, E
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.10.1999; Springer Nature B.V
• Subjects: Animals; Antianginal agents. Coronary vasodilator agents; Aorta - drug effects; Aorta - metabolism; Binding Sites - drug effects; Binding, Competitive - drug effects; Biological and medical sciences; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - drug effects; Cardiovascular system; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Diltiazem - analogs & derivatives; Diltiazem - pharmacology; Guinea Pigs; In Vitro Techniques; Ligands; Medical sciences; Models, Molecular; Molecular Conformation; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Pharmacology. Drug treatments; Quinazolines - pharmacology; Quinazolinones; Rabbits; Structure-Activity Relationship; Antianginal agent; Structure activity relation; Coronary vasodilator agent; Quinazoline derivatives; Benzothiazepine derivatives; Ionic channel; Diltiazem; Modeling; Structural analysis; Calcium Cations; Conformation
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1015037800903

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.