title: Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.
abstract: The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.
authors.affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, ⊥Department of Oncology, and ∥Department of Physics, University of Alberta , Edmonton, AB, Canada T6G 2E1.
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.forename: John
authors.initials: J
authors.lastname: Law
authors.forename: Alessio
authors.initials: A
authors.lastname: Prunotto
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Magee
authors.forename: David H
authors.initials: DH
authors.lastname: Evans
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005838:Genotype; D016174:Hepacivirus / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry*; D011485:Protein Binding; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012107:Research Design; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009711:Nucleotides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase