title: Screening of hepatitis C NS5B polymerase inhibitors containing benzothiadiazine core: a steered molecular dynamics.
abstract: Hepatic C virus (HCV) is a global health problem, resulting in liver cirrhosis and inflammation that can develop to hepatocellular carcinoma and fatality. The NS5B polymerase of HCV plays an important role in viral RNA replication process, making it an attractive therapeutic target for design and development of anti-HCV drugs. To search new potent compounds against the HCV NS5B polymerase, the molecular docking and the steered molecular dynamics (SMD) simulation techniques were performed. The potential potent inhibitors of the NS5B polymerase were screened out from the ZINC database using structural similarity search and molecular docking technique. Five top-hit compounds (the ZINC compounds 49888724, 49054741, 49777239, 49793673, and 49780355) were then studied by the SMD simulations based on the hypothesis that a high rupture force relates to a high binding efficiency. The results demonstrated that the ZINC compound 49888724 had a greater maximum rupture force, reflecting a good binding strength and inhibitory potency than known inhibitors and the rest four ZINC compounds. Therefore, our finding indicated that the ZINC compound 49888724 is a potential candidate to be a novel NS5B inhibitor for further design. Besides, the van der Waals interaction could be considered as the main contribution for stabilizing the NS5B-ligand complex.
authors.affiliation: a Program in Biotechnology, Faculty of Science , Chulalongkorn University , Bangkok 10330 , Thailand.
authors.forename: Bodee
authors.initials: B
authors.lastname: Nutho
authors.affiliation: b Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science , Chulalongkorn University , Bangkok 10330 , Thailand.
authors.forename: Arthitaya
authors.initials: A
authors.lastname: Meeprasert
authors.affiliation: b Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science , Chulalongkorn University , Bangkok 10330 , Thailand.
authors.forename: Methat
authors.initials: M
authors.lastname: Chulapa
authors.affiliation: c Department of Chemistry, Faculty of Science , Chiang Mai University , Chiang Mai 50200 , Thailand.
authors.forename: Nawee
authors.initials: N
authors.lastname: Kungwan
authors.affiliation: b Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science , Chulalongkorn University , Bangkok 10330 , Thailand.|d PhD Program in Bioinformatics and Computational Biology, Faculty of Science , Chulalongkorn University , Bangkok 10330 , Thailand.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
mesh_terms: D020816:Amino Acid Motifs; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism; D001581:Benzothiadiazines / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D062126:Databases, Chemical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D016174:Hepacivirus / Q000737:chemistry* / Q000201:enzymology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: NS5B polymerase; hepatitis C virus; molecular docking; steered molecular dynamics simulations