title: LuxR-dependent quorum sensing: computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones.
abstract: A virtual screening, involving flexible docking sequences within the LuxR, TraR and LasR binding sites, was used as a structural binding sites similarity filter to specifically target conserved residues in the proteins of the LuxR family (namely Tyr62, Trp66, Tyr70, Asp79, Trp94 for LuxR). This docking-based screening, employing a genetic algorithm, was performed on a 2344 chemical compounds library, together with empirical binding free energy (DeltaG(bind)) calculations. Docking results were analysed, and the compounds detected with reproducible low DeltaG(bind) values or identified as being in the top 120 for most of the docking sequences, were selected as hits candidates which interact with conserved residues. Biological evaluation with LuxR-dependent quorum sensing led to the discovery of some new inhibitors, namely tamoxifen, sertraline, pimethixene, terfenadine, fendiline and calmidazolium. Notably, calmidazolium was identified as one of the most potent AHL-structurally unrelated inhibitors of LuxR-dependent quorum sensing, with an IC(50) value of 7.0+/-0.2 microM.
authors.affiliation: INSA Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique, Bât J. Verne, Villeurbanne Cedex, France. laurent.soulere@insa-lyon.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Soulère
authors.forename: Mohamad
authors.initials: M
authors.lastname: Sabbah
authors.forename: Fanny
authors.initials: F
authors.lastname: Fontaine
authors.forename: Yves
authors.initials: Y
authors.lastname: Queneau
authors.forename: Alain
authors.initials: A
authors.lastname: Doutheau
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000494:pharmacology; D053038:Quorum Sensing / Q000187:drug effects*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D007093:Imidazoles; D012097:Repressor Proteins; D054852:Small Molecule Libraries; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; C088386:homoserine lactone; C031938:calmidazolium; D015107:4-Butyrolactone