title: Discovery of potent inhibitors targeting Vibrio harveyi LuxR through shape and e-pharmacophore based virtual screening and its biological evaluation.
abstract: Quorum sensing is widely recognized as an efficient mechanism in the regulation and production of several virulence factors, biofilm formation and stress responses. For this reason, quorum sensing circuit is emerging as a novel drug target for the development of anti-infective. Recently, cinnamaldehyde derivatives have been found to interfere with master quorum sensing transcriptional regulator and thereby decreasing the DNA binding ability of LuxR. However, the exact mode of cinnamaldehyde binding with LuxR and receptor interaction still remains inconclusive. In the current study, combined method of molecular docking and molecular dynamics simulations were performed to investigate the binding mode, dynamic and energy aspects of cinnamaldehyde derivatives into the binding site of LuxR. Based on the experimental and computational evidences, LuxR-3,4-dichloro-cinnamaldehyde complex was chosen for the development of e-pharmacophore model. Further, shape and e-pharmacophore based virtual screening were performed against ChemBridge database to find potent and suitable ligands for LuxR. By comparing the results of shape and e-pharmacophore based virtual screening; best 9 hit molecules were selected for further studies including ADMET prediction, molecular dynamics simulations and Prime MM-GBSA calculations. From the 9 hit molecules, the top most compound 3-(2,4-dichlorophenyl)-1-(1H-pyrrol-2-yl)-2-propen-1-one (ChemBridge-7364106) was selected for in vitro assays using Vibrio harveyi. The result revealed that ChemBridge-7364106 significantly reduced the bioluminescence production in a dose dependent manner. In addition, ChemBridge-7364106 showed a significant inhibition in biofilm formation and motility in V. harveyi. The results from the study suggest that ChemBridge-7364106 could serve as an anti-quorum sensing molecule for V. harveyi.
authors.affiliation: Department of Bioinformatics, Science campus Alagappa University, Karaikudi, Tamilnadu, India.
authors.forename: Sundaraj
authors.initials: S
authors.lastname: Rajamanikandan
authors.affiliation: Department of Bioinformatics, Science campus Alagappa University, Karaikudi, Tamilnadu, India.
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Jeyakanthan
authors.affiliation: Department of Animal Health and Management, Science campus Alagappa University, Karaikudi, Tamilnadu, India. Electronic address: sri.bioinformatics@gmail.com.
authors.forename: Pappu
authors.initials: P
authors.lastname: Srinivasan
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012997:Solvents; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014733:Vibrio / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D012097:Repressor Proteins; D012997:Solvents; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins
keywords: In vitro assays; Quorum sensing; Shape based virtual screening; Vibrio harveyi; e-Pharmacophore