Lead identification for modulators of multidrug resistance based on in silico screening with a pharmacophoric feature model

Author(s)

Thierry Langer, Monika Eder, Remy D. Hoffmann, Peter Chiba, Gerhard Ecker

Abstract

Considerable effort has been devoted to the characterization of P-glycoprotein - drug interaction in the past. Systematic quantitative structure-activity relationship (QSAR) studies identified both predictive physicochemical parameters and pharmacophoric substructures within homologous series of compounds. Comparative molecular field analysis (CoMFA) led to distinct 3D-QSAR models for propafenone and phenothiazine analogs. Recently, several pharmacophore models have been generated for diverse sets of ligands. Starting from a training set of 15 propafenone-type MDR-modulators, we established a chemical function-based pharmacophore model. The pharmacophoric features identified by this model were (i) one hydrogen bond acceptor, (ii) one hydrophobic area, (iii) two aromatic hydrophobic areas, and (iv) one positive ionizable group. In silica screening of the Derwent World Drug Index using the model led to identification of 28 compounds. Substances retrieved by database screening are diverse in structure and include dihydropyridines, chloroquine analogs, phenothiazines, and terfenadine. On the basis of its general applicability, the presented 3D-QSAR model allows in silica screening of virtual compound libraries to identify new potential lead compounds.

Organisation(s)

External organisation(s)

Leopold-Franzens-Universität Innsbruck

Journal

Archiv der Pharmazie

Volume

337

Pages

317-327

No. of pages

11

ISSN

0365-6233

Publication date

2004

Peer reviewed

Yes

Austrian Fields of Science 2012

3012 Pharmacy, Pharmacology, Toxicology

Portal url

https://ucris.univie.ac.at/portal/en/publications/lead-identification-for-modulators-of-multidrug-resistance-based-on-in-silico-screening-with-a-pharmacophoric-feature-model(9aae6607-7a87-4309-8001-63f35300025b).html