title: A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds.
abstract: Nitrile-based inhibitors of cathepsin K have been known for some time and mechanism-of-action studies have demonstrated that cysteinyl proteases interact with nitriles in a reversible fashion. Three main classes of nitrile-containing inhibitors have been published in the cathepsin K field: (i) cyanamides, (ii) aromatic nitriles, and (iii) aminoacetonitriles. A computational approach was used to calculate the theoretical reactivities of diverse nitriles and this was found to correlate with their extent of reactivity with free cysteine. Moreover, there is a tentative link between high reactivity with cysteine and the potential to lead to irreversible covalent binding to proteins.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Que., Canada H9H 3L1. renata_oballa@merck.com
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Truchon
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Stephen
authors.initials: S
authors.lastname: Day
authors.forename: Sheldon
authors.initials: S
authors.lastname: Crane
authors.forename: Carl
authors.initials: C
authors.lastname: Berthelette
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors; D019295:Computational Biology; D003545:Cysteine / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004563:Electrochemistry; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry*; D010084:Oxidation-Reduction
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D009249:NADP; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D003545:Cysteine