Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase

J Med Chem. 2009 Jul 23;52(14):4099-102. doi: 10.1021/jm9005548.

Abstract

HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Benzodiazepines / chemistry*
  • Benzodiazepines / pharmacology*
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / enzymology*
  • Models, Molecular
  • Molecular Conformation
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Viral Nonstructural Proteins
  • Benzodiazepines
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase

Associated data

  • PDB/3GNV
  • PDB/3GNW