title: Rational Drug Discovery of HCV Helicase Inhibitor: Improved Docking Accuracy with Multiple Seeding in AutoDock Vina and In Situ Minimization.
abstract: BACKGROUND
  Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximately 3% of the global populations. Despite the current several direct antiviral agents in the treatment of Hepatitis C, the standard treatment for HCV infection is accompanied by several drawbacks, such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants.
  
  
  OBJECTIVE
  To discover potential inhibitors for HCV helicase through an optimized in silico approach.
  
  
  METHODS
  In this study, a homology model (HCV Genotype 3 helicase) was used as the target and screened through a benzopyran-based virtual library. Multiple-seedings of AutoDock Vina and in situ minimization were to account for the non-deterministic nature of AutoDock Vina search algorithm and binding site flexibility, respectively. ADME/T and interaction analyses were also done on the top hits via FAFDRUG3 web server and Discovery Studio 4.5.
  
  
  RESULTS
  This study involved the development of an improved flow for virtual screening via implemention of multiple-seeding screening approach and in situ minimization. With the new docking protocol, the redocked standards have shown better RMSD value in reference to their native conformations. Ten benzopyran-like compounds with satisfactory physicochemical properties were discovered to be potential inhibitors of HCV helicase. ZINC38649350 was identified as the most potential inhibitor.
  
  
  CONCLUSIONS
  Ten potential HCV helicase inhibitors were discovered via a new docking optimization protocol with better docking accuracy. These findings could contribute to the discovery of novel HCV antivirals and serve as an alternative approach of in silico rational drug discovery.
authors.affiliation: Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia.|Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: See K
authors.initials: SK
authors.lastname: Lim
authors.affiliation: Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia.|Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Rozana
authors.initials: R
authors.lastname: Othman
authors.affiliation: Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia.|Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Rohana
authors.initials: R
authors.lastname: Yusof
authors.affiliation: Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia.|Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Choon H
authors.initials: CH
authors.lastname: Heh
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D017076:Computer-Aided Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D062105:Molecular Docking Simulation; D012984:Software; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001578:Benzopyrans; D004791:Enzyme 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
keywords: Antiviral agents; AutoDock Vina; Hepatitis C virus genotype 3; NS3 helicase; benzopyran; virtual screening.