title: Binding mode exploration of LuxR-thiazolidinedione analogues, e-pharmacophore-based virtual screening in the designing of LuxR inhibitors and its biological evaluation.
abstract: 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.
authors.affiliation: a Department of Bioinformatics , Alagappa University , Karaikudi , TamilNadu , India.
authors.forename: Sundaraj
authors.initials: S
authors.lastname: Rajamanikandan
authors.affiliation: a Department of Bioinformatics , Alagappa University , Karaikudi , TamilNadu , India.
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Jeyakanthan
authors.affiliation: a Department of Bioinformatics , Alagappa University , Karaikudi , TamilNadu , India.|b Department of Animal Health and Management , Alagappa University , Karaikudi , TamilNadu , India.
authors.forename: Pappu
authors.initials: P
authors.lastname: Srinivasan
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D053038:Quorum Sensing; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014733:Vibrio / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D045162:Thiazolidinediones; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; C089946:2,4-thiazolidinedione
keywords: LuxR; molecular docking; molecular dynamics simulations; quorum sensing; thiazolidinedione analogues