| Title | A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases. | ||
| Author | Kathman, Stefan G; Xu, Ziyang; Statsyuk, Alexander V | ||
| Journal | J Med Chem | Publication Year/Month | 2014-Jun |
| PMID | 24870364 | PMCID | PMC4113264 |
| Affiliation | 1.Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University , 2170 Campus Drive, Evanston, Illinois 60208, United States. | ||
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.