Beta-amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors

Bioorganic & Medicinal Chemistry
Johanna NurboAnja Sandström

Abstract

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 h...Continue Reading

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Citations

Feb 9, 2011·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Bokyung KimHyun Ho Park
Feb 2, 2012·AMB Express·Jens RudatChristoph Syldatk
Feb 26, 2019·Protein Science : a Publication of the Protein Society·Sunghark Kwon, Hyun H Park
Aug 31, 2012·Chemical Communications : Chem Comm·Zhenjun MaoXufeng Lin

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