title: 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.
authors.affiliation: 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.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Kathman
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Xu
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Statsyuk
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000179:Acrylates / Q000737:chemistry; D000977:Antiparasitic Agents / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010206:Papain / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012229:Rhinovirus / Q000201:enzymology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors; D014753:Vinyl Compounds / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors
chemical_list: D000178:Acrylamides; D000179:Acrylates; D000977:Antiparasitic Agents; D015853:Cysteine Proteinase Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D013450:Sulfones; D014753:Vinyl Compounds; D014764:Viral Proteins; D044763:Ubiquitin-Conjugating Enzymes; D064570:Ubiquitin-Specific Proteases; D010206:Papain