title: Dual Allosteric Inhibitors Jointly Modulate Protein Structure and Dynamics in the Hepatitis C Virus Polymerase.
abstract: The hepatitis C virus (HCV) infects close to 200 million people globally, resulting in a significant need for effective HCV therapies. The HCV polymerase (gene product NS5B) is a valuable target for therapeutics because of its role in replicating the viral genome. Various studies have identified inhibitors for this enzyme, including non-nucleoside inhibitors (NNIs) that bind distal to the enzyme active site. Recently, it has been shown that simultaneously challenging the enzyme with two NNIs results in enhanced inhibition relative to that observed after challenge with individual inhibitors, suggesting that employing multiple NNIs might be the basis of more effective therapeutics. Nevertheless, the molecular mechanisms responsible for this enhanced inhibition remain unclear. We employ molecular dynamics simulations to determine the origin of enhanced inhibition when two NNIs bind to NS5B. Our results suggest that nonoverlapping NNI sites are compatible with simultaneous binding of dual NNIs. We observe that both inhibitors act in concert to induce novel enzyme conformations and dynamics, allowing us to identify molecular mechanisms underlying enhanced inhibition of NS5B. This knowledge will be useful in optimizing combinations of NNIs to target NS5B, helping to prevent the acquisition of viral resistance that remains a significant barrier to the development of HCV therapeutics.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States.
authors.forename: Jodian A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Thorpe
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase