LuxR-dependent quorum sensing: Computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones

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 (ΔG_bind) calculations. Docking results were analysed, and the compounds detected with reproducible low ΔG_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 IC₅₀ value of 7.0 ± 0.2 μM.