Source:http://linkedlifedata.com/resource/pubmed/id/18434166
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
10
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pubmed:dateCreated |
2008-5-26
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/NS3 protein, hepatitis C virus,
http://linkedlifedata.com/resource/pubmed/chemical/Protease Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Viral Nonstructural Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1464-3391
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
16
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5590-605
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pubmed:meshHeading |
pubmed-meshheading:18434166-Amino Acids,
pubmed-meshheading:18434166-Drug Evaluation, Preclinical,
pubmed-meshheading:18434166-Ligands,
pubmed-meshheading:18434166-Models, Molecular,
pubmed-meshheading:18434166-Molecular Structure,
pubmed-meshheading:18434166-Protease Inhibitors,
pubmed-meshheading:18434166-Quantitative Structure-Activity Relationship,
pubmed-meshheading:18434166-Stereoisomerism,
pubmed-meshheading:18434166-Viral Nonstructural Proteins
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pubmed:year |
2008
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pubmed:articleTitle |
Beta-amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors.
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pubmed:affiliation |
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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