LuxR-dependent quorum sensing: Computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones |
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Authors: | Laurent Soulère Mohamad Sabbah Fanny Fontaine Yves Queneau Alain Doutheau |
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Affiliation: | INSA Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique, Bât J. Verne, 20 av A. Einstein, 69621 Villeurbanne Cedex, France;CNRS, UMR 5246 ICBMS, Université Lyon 1, INSA-Lyon, CPE-Lyon, Bât CPE, 43 bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France |
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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 (ΔGbind) calculations. Docking results were analysed, and the compounds detected with reproducible low ΔGbind 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 IC50 value of 7.0 ± 0.2 μM. |
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