Abstract
This work describes the use of NMR as a medicinal chemistry tool for better understanding the binding characteristics of inhibitors of the HCV NS3 protease. The protease-bound structure of a tetrapeptide-like inhibitor that has an acid C-terminus, a norvaline at P1 and a naphthylmethoxy proline at P2 is described. Conformational comparisons are made with a similar compound having a 1-amino-cyclopropylcarboxylic acid at P1 and with a hexapeptide inhibitor. Differences between the free and bound states are identified. 19F NMR also helped in determining that a single complex is observed when an inhibitor is added to the protease at a 1:1 ratio.
MeSH terms
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Hepacivirus / drug effects
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Hepacivirus / enzymology*
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Molecular Conformation
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Nuclear Magnetic Resonance, Biomolecular / methods
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Oligopeptides / chemistry*
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Oligopeptides / pharmacology
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Protein Conformation
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Serine Endopeptidases / chemistry*
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Serine Endopeptidases / metabolism
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Serine Proteinase Inhibitors / chemistry*
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry*
Substances
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NS3 protein, hepatitis C virus
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NS4 protein, hepatitis C virus
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Oligopeptides
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Serine Endopeptidases