NDLI: Molecular Modeling Study of Diltiazem Mimics at L-Type Calcium Channels

Content Provider	Springer Nature Link
Author	Schleifer, Klaus Jürgen Tot, Edith
Copyright Year	1999
Abstract	Purpose. 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. Methods. Via molecular mechanics and quantum chemical methods solvation energies, logP values, conformational and electronic features of classical l,5-benzothiazepin-4(5H)-one (BTZ, e.g., diltiazem), 1-benzazepin-2-one (BZ), pyrrolo [2,1-d][1,5 ]benzothiazepine, pyrrolo[2,l-c][l,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. Results. This yielded a pharmacophore model with three crucial pharmacophoric characteristics, (1) two aromatic ring systems in a distance of about 6.7 Å, (2) a basic side chain with pK$_{a}$ 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. Conclusions. Based on these molecular descriptors, the quinazolinone derivative MCI-176 is predicted to be a potential ligand of the diltiazem binding site.
Starting Page	1506
Ending Page	1513
Page Count	8
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	16
Issue Number	10
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	1999-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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