Abstract
A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. We attached an electrophile to 100 fragments without significant alterations in the reactivity of the electrophile. A mass spectrometry assay discovered three nonpeptidic inhibitors of the cysteine protease papain. The identified compounds display the characteristics of irreversible inhibitors. The irreversible tethering system also displays specificity: the three identified papain inhibitors did not covalently react with UbcH7, USP08, or GST-tagged human rhinovirus 3C protease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemistry
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Acrylates / chemistry
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Antiparasitic Agents / chemistry
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Cysteine Proteinase Inhibitors / chemistry*
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Drug Design*
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Humans
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Models, Molecular
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Papain / antagonists & inhibitors*
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Papain / chemistry
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Rhinovirus / enzymology
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Small Molecule Libraries
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfones / chemistry
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Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
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Ubiquitin-Specific Proteases / antagonists & inhibitors
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Vinyl Compounds / chemistry
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Viral Proteins / antagonists & inhibitors
Substances
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Acrylamides
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Acrylates
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Antiparasitic Agents
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Cysteine Proteinase Inhibitors
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Small Molecule Libraries
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Sulfonamides
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Sulfones
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Vinyl Compounds
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Viral Proteins
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Ubiquitin-Conjugating Enzymes
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Ubiquitin-Specific Proteases
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Papain