Targeting drug-efflux pumps -- a pharmacoinformatic approach

• Published in: Acta biochimica polonica Vol. 52; no. 3; pp. 737 - 740
• Main Authors: Pleban, Karin, Kaiser, Dominik, Kopp, Stefan, Peer, Michael, Chiba, Peter, Ecker, Gerhard F
• Format: Journal Article
• Language: English
• Published: Poland 01.01.2005
• Subjects: Anti-Arrhythmia Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Catalysis; Drug Design; Ligands; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; Neural Networks, Computer; Photoaffinity Labels - chemistry; Photoaffinity Labels - metabolism; Propafenone - pharmacology; Protein Binding; Protein Conformation
• DOI: 10.18388/abp.2005_3439
• ISSN: 0001-527X

In line with our studies on propafenone-type inhibitors of P-glycoprotein (P-gp), we applied several methods to approach virtual screening tools for identification of new P-gp inhibitors on one hand and the molecular basis of ligand-protein interaction on the other hand. For virtual screening, a combination of autocorrelation vectors and selforganising artificial neural networks proved extremely valuable in identifying P-gp inhibitors with structurally new scaffolds. For a closer view on the binding region for propafenone-type ligands we applied a combination of pharmacophore-driven photoaffinity labeling and protein homology modeling. On LmrA, a bacterial homologue of P-gp, we were able to identify distinct regions on transmembrane helices 3, 5 and 6 which show significant changes in the labeling pattern during different steps of the catalytic cycle.