Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization

J Med Chem. 2007 May 17;50(10):2310-8. doi: 10.1021/jm060173k. Epub 2007 Apr 20.


The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Binding Sites
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / chemistry*
  • Crystallography, X-Ray
  • Hepacivirus / enzymology*
  • Intracellular Signaling Peptides and Proteins
  • Models, Molecular
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / chemistry
  • Protein Conformation
  • Serine Proteinase Inhibitors / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry*
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry*


  • Antiviral Agents
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Viral Proteins
  • N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
  • Proline