Abstract
The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (K(i) 30 nM) and reversible covalent inhibitors (6, K(i) 0.5 nM; and 8 K*(i) 10 pM).
MeSH terms
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Cysteine*
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Drug Design
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Hepacivirus / enzymology*
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Humans
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Models, Molecular*
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Molecular Mimicry
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Oligopeptides / chemical synthesis*
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Oligopeptides / pharmacology
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
Substances
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NS3 protein, hepatitis C virus
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Oligopeptides
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Viral Nonstructural Proteins
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Cysteine