Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition

J Med Chem. 2014 Dec 11;57(23):10031-43. doi: 10.1021/jm501291c. Epub 2014 Nov 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / pharmacology
  • Hepacivirus / drug effects
  • Imidazoles / metabolism*
  • Imidazoles / pharmacology
  • Molecular Docking Simulation
  • Sequence Alignment
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Imidazoles
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • daclatasvir