Binding mode exploration of LuxR-thiazolidinedione analogues, e-pharmacophore-based virtual screening in the designing of LuxR inhibitors and its biological evaluation

摘要

Master quorum sensing (QS) regulator LuxR of Vibrio harveyi is a unique member of the TetR protein superfamily. Recent studies have demonstrated the contribution of thiazolidinedione analogues in blocking QS by decreasing the DNA-binding ability of LuxR. However, the precise mechanism of thiazolidinedione analogues binding to LuxR is still unclear. In the present study, molecular docking combined with molecular dynamics (MD) simulations was performed to understand the mechanism of ligand binding to the protein. The binding pattern of thiazolidinedione analogues showed strong hydrogen bonding interactions with the amine group (NH) of polar amino acid residue Asn133 and carbonyl (C-O) interaction with negatively charged amino acid residue Gln137 in the binding site of LuxR. The stability of the protein-ligand complexes was confirmed by running 50 ns of MD simulations. Further, the four-featured pharmacophore hypothesis (AHHD) consists of one acceptor (A), two hydrophobic regions (HH) and one donor (D) group was used to screen compounds from ChemBridge database. The identified hit molecules were shown to have excellent pharmacokinetic properties under the acceptable range. Based on the computational studies, ChemBridge_5343641 was selected for in vitro assays. The 1-(4-chlorophenoxy)-3-[(4,6-dimethyl-2-pyrimidinyl) thio]-2-propanol (ChemBridge_ 5343641) showed significant reduction in bioluminescence in a dose-dependent manner. In addition, ChemBridge_ 5343641 inhibits biofilm formation and motility in V. harveyi. The result from the study suggests that ChemBridge_ 5343641 could serve as an anti-QS molecule.