کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1360915 981452 2008 16 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
چکیده انگلیسی

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 P1, P2, and P3 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 P3 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 q2 = 0.48 and rpred2=0.68.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 10, 15 May 2008, Pages 5590–5605
نویسندگان
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