title: In silico screening for potent inhibitors against the NS3/4A protease of hepatitis C virus.
abstract: Hepatitis C virus (HCV) infections are a serious viral health problem globally, causing liver cirrhosis and inflammation that can develop to hepatocellular carcinoma and death. Since the HCV NS3/4A protease complex cleaves the scissile peptide bond in the viral encoded polypeptide to release the non-structural proteins during the viral replication process, this protease is then an important target for drug design. The computer-aided drug design and screening targeted at NS3/4A protease of HCV were reviewed. In addition, using steered molecular dynamics simulations, potent inhibitors of the NS3/4A complex were searched for by screening the ZINC database based upon the hypothesis that a high rupture force indicates a high binding efficiency. Nine top-hit compounds (59500093, 59784724, 13527817, 26660256, 29482733, 25977181, 28005928, 13527826 and 13527826) were found that had the same or a greater maximum rupture force (and so assumed binding strength and inhibitory potency) than the four current drugs and so are potential candidates as anti- HCV chemotherapeutic agents. In addition, van der Waals interactions were found to be the main contribution in stabilizing the ligand- NS3/4A complex.
authors.forename: Arthitaya
authors.initials: A
authors.lastname: Meeprasert
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Mai Suan
authors.initials: MS
authors.lastname: Li
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand. masli@ifpan.edu.pl.
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases