title: Targeting drug-efflux pumps -- a pharmacoinformatic approach.
abstract: 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.
authors.affiliation: Emerging Focus Pharmacoinformatics, Department of Medicinal Chemistry, University of Vienna, Wien, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Pleban
authors.forename: Dominik
authors.initials: D
authors.lastname: Kaiser
authors.forename: Stefan
authors.initials: S
authors.lastname: Kopp
authors.forename: Michael
authors.initials: M
authors.lastname: Peer
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002384:Catalysis; D015195:Drug Design; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016571:Neural Networks, Computer; D019920:Photoaffinity Labels / Q000737:chemistry / Q000378:metabolism*; D011405:Propafenone / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D001426:Bacterial Proteins; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019920:Photoaffinity Labels; D011405:Propafenone; C101824:LmrA protein, Lactococcus lactis