title: Structure based virtual screening for identification of potential quorum sensing inhibitors against LasR master regulator in Pseudomonas aeruginosa.
abstract: Inter and intracellular communication in bacteria, which is known as quorum sensing (QS), is mediated by small diffusible signaling molecules known as autoinducers. QS regulates various virulence factors responsible for pathogenesis. Increasing resistance of microorganisms against traditional antibiotics has turned the focus towards the QS as it exerts less selective pressure preventing development of resistance among microorganisms. LasR, a transcription factor that controls QS in Pseudomonas aeruginosa, is an attractive therapeutic target for inhibitors. This study aimed to screen natural compounds as potential inhibitors of LasR. About 2603 compounds from ZINC database were virtually screened against the structure of LasR. Then after qualifying compounds were filtered on the parameters of Lipinski's rule and ADME. Six novel potential QS inhibiting compounds were selected on the basis of binding energy. Structures of LasR-ligand complexes were analysed to have insight of binding between inhibitors and target. It is pertinent to mention here that all the molecules are structurally different from 3-oxo-C12HSL,a native autoinducer of LasR, that play key role in formation of LasR dimer which is an active form of the protein to facilitate QS.
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Manmohit
authors.initials: M
authors.lastname: Kalia
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Yadav
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Birendra Singh
authors.initials: BS
authors.lastname: Yadav
authors.affiliation: Department of Mathematics, National Institute of Technology, Raipur, India.
authors.forename: Deepmala
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Sahid Suhail
authors.initials: SS
authors.lastname: Narvi
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mani
authors.affiliation: Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India. Electronic address: vishnua@mnnit.ac.in.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Agarwal
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D055598:Chemical Phenomena; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006714:Homoserine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D015534:Trans-Activators / Q000737:chemistry* / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D014584:User-Computer Interface; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; C109860:N-(3-oxododecanoyl)homoserine lactone; D015534:Trans-Activators; D014157:Transcription Factors; D037521:Virulence Factors; D006714:Homoserine; D015107:4-Butyrolactone
keywords: ADME; Lipinski rule; Molecular docking; P. aeruginosa; Quorum sensing inhibitors; Virtual screening