title: A Comprehensive Computational Analysis for the Binding Modes of Hepatitis C Virus NS5A Inhibitors: The Question of Symmetry.
abstract: Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origin of resistance to these drugs.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Marawan
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Indian Institute of Technology , Kharagpur, West Bengal 721302, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Pal
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.|Li Ka Shing Applied Virology Institute, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.|Li Ka Shing Institute of Virology, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.|Li Ka Shing Applied Virology Institute, University of Alberta , 116 Street & 85 Avenue, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002219:Carbamates; D019295:Computational Biology; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D010750:Phosphoproteins; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; C532378:nonstructural phosphoprotein 5A, GB virus type C; D014633:Valine; C549273:daclatasvir
keywords: Daclatasvir (DCV); HCV; NS5A; NS5A mutations; asymmetric ligands; direct-acting antivirals; symmetric ligands