A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds.
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.
Oballa
Renata M
RM
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Que., Canada H9H 3L1. renata_oballa@merck.com
Truchon
Jean-François
JF
Bayly
Christopher I
CI
Chauret
Nathalie
N
Day
Stephen
S
Crane
Sheldon
S
Berthelette
Carl
C
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
D015853:Cysteine Proteinase Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D009249:NADP; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D003545:Cysteine