β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 16, no 10, 5590-5605 p.Article in journal (Refereed) Published
In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-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 alpha-peptide analogues. However, several compounds exhibited muM 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 beta-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.
Place, publisher, year, edition, pages
2008. Vol. 16, no 10, 5590-5605 p.
hepatitis C, HCV, NS3, protease inhibitor, beta-amino acid, 3D-QSAR, CoMFA, docking
IdentifiersURN: urn:nbn:se:uu:diva-96053DOI: 10.1016/j.bmc.2008.04.005ISI: 000256052400023PubMedID: 18434166OAI: oai:DiVA.org:uu-96053DiVA: diva2:170498