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A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases.

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.

SUBMITTER: Kathman SG

PROVIDER: S-EPMC4113264 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases.

Kathman Stefan G SG Xu Ziyang Z Statsyuk Alexander V AV

Journal of medicinal chemistry 20140528 11

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 ide ...[more]

PMID: 24870364

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