Detailed Computational Study of the Active Site of the Hepatitis C Viral RNA Polymerase to Aid Novel Drug Design

• Published in: Journal of chemical information and modeling Vol. 53; no. 11; pp. 3031 - 3043
• Main Authors: Barakat, Khaled H, Law, John, Prunotto, Alessio, Magee, Wendy C, Evans, David H, Tyrrell, D. Lorne, Tuszynski, Jack, Houghton, Michael
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.11.2013
• Subjects: Amino Acid Sequence; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Biological and medical sciences; Catalytic Domain; Drug Design; Drug Discovery; Enzyme Inhibitors - chemistry; Enzymes; General pharmacology; Genotype; Hepacivirus - chemistry; Hepatitis; Hepatitis C; Medical sciences; Molecular Dynamics Simulation; Molecular Mimicry; Molecular Sequence Data; Molecular structure; Nucleotides - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Binding; Research Design; RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; Sequence Alignment; Sequence Homology, Amino Acid; Simulation; Structure-Activity Relationship; Thermodynamics; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Pharmaceutical technology; RNA; Enzyme; Active site; Genotype; Pharmacology; Modeling; Free energy; Virus; Screening; Molecular physics; Binding energy; Biopolymer; Antiviral; Genetics; Genome; Pharmaceutical industry; Statistical mechanics
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci4003969

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.