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β-Amino acid substi...
β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
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- Nurbo, Johanna (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Peterson, Shane D. (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Dahl, Göran (author)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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- Danielson, U. Helena (author)
- Uppsala universitet,Institutionen för biokemi och organisk kemi
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- Karlén, Anders (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Sandström, Anja (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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(creator_code:org_t)
- Elsevier BV, 2008
- 2008
- English.
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:10, s. 5590-5605
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- hepatitis C
- HCV
- NS3
- protease inhibitor
- beta-amino acid
- 3D-QSAR
- CoMFA
- docking
- PHARMACY
- FARMACI
Publication and Content Type
- ref (subject category)
- art (subject category)
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