title: Structural insights on identification of potential lead compounds targeting WbpP in Vibrio vulnificus through structure-based approaches.
abstract: WbpP encoding UDP-GlcNAC C4 epimerase is responsible for the activation of virulence factor in marine pathogen Vibrio vulnificus (V. vulnificus) and it is linked to many aquatic diseases, thus making it a potential therapeutic target. There are few reported compounds that include several natural products and synthetic compounds targeting Vibrio sp, but specific inhibitor targeting WbpP are unavailable. Here, we performed structure-based virtual screening using chemical libraries such as Binding, TOSLab and Maybridge to identify small molecule inhibitors of WbpP with better drug-like properties. Deficient structural information forced to model the structure and the stable protein structure was obtained through 30 ns of MD simulations. Druggability regions are focused for new lead compounds and our screening protocol provides fast docking of entire small molecule library with screening criteria of ADME/Lipinski filter/Docking followed by re-docking of top hits using a method that incorporates both ligand and protein flexibility. Docking conformations of lead molecules interface displays strong H-bond interactions with the key residues Gly101, Ser102, Val195, Tyr165, Arg298, Val209, Ser142, Arg233 and Gln200. Subsequently, the top-ranking compounds were prioritized using the molecular dynamics simulation-based conformation and stability studies. Our study suggests that the proposed compounds may aid as a starting point for the rational design of novel therapeutic agents.
authors.affiliation: a Science Block, Department of Bioinformatics, Alagappa University , Karaikudi, Tamil Nadu , India and.
authors.forename: Dakshinamurthy
authors.initials: D
authors.lastname: Sasikala
authors.affiliation: a Science Block, Department of Bioinformatics, Alagappa University , Karaikudi, Tamil Nadu , India and.
authors.forename: Jeyaraman
authors.initials: J
authors.lastname: Jeyakanthan
authors.affiliation: b Science Block, Department of Animal Health and Management, Alagappa University , Karaikudi, Tamil Nadu , India.
authors.forename: Pappu
authors.initials: P
authors.lastname: Srinivasan
mesh_terms: D059001:Aquatic Organisms / Q000235:genetics / Q000382:microbiology / Q000472:pathogenicity; D001665:Binding Sites; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D005517:Foodborne Diseases / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D007854:Lead / Q000737:chemistry* / Q000627:therapeutic use; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D041261:Vibrio vulnificus / Q000737:chemistry* / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D007854:Lead; D002238:Carbohydrate Epimerases; C023223:UDP-N-acetylglucosamine 4-epimerase
keywords: ADME properties; UDP-GlcNAC C4 epimerase; Vibrio vulnificus; molecular docking; molecular dynamics