title: Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
abstract: Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
authors.affiliation: Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: Nettles
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stanton
authors.forename: Joshua
authors.initials: J
authors.lastname: Broyde
authors.forename: Franck
authors.initials: F
authors.lastname: Amblard
authors.forename: Hongwang
authors.initials: H
authors.lastname: Zhang
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.forename: Junxing
authors.initials: J
authors.lastname: Shi
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Tony
authors.initials: T
authors.lastname: Whitaker
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Coats
authors.forename: James J
authors.initials: JJ
authors.lastname: Kohler
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D002219:Carbamates; D016174:Hepacivirus / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011759:Pyrrolidines; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir