Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease

Bioorg Med Chem Lett. 2001 Sep 3;11(17):2355-9. doi: 10.1016/s0960-894x(01)00457-7.

Abstract

A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn(2+)-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn(2+), with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Biochemistry / methods
  • Drug Evaluation, Preclinical
  • Hepacivirus / enzymology*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology*
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Zinc / metabolism*

Substances

  • APC 6336
  • Antiviral Agents
  • Benzimidazoles
  • NS3 protein, hepatitis C virus
  • Organophosphonates
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Zinc