β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors

Abstract

In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of α- and β-amino acids has been synthesized. To understand the structural implications of β-amino acid substitution, the P 1, P 2, and P 3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the α-peptide analogues. However, several compounds exhibited μM potency. Inhibition data were compared with modeled ligand–protein binding poses to understand how changes in ligand structure affected inhibition potency. The P 3 position seemed to be the least sensitive position for β-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q 2 = 0.48 and r pred 2 = 0.68 .