Biomolecular soft nucleophiles

Biomolecular soft nucleophiles are chemical functional groups within biological molecules, such as the sulfhydryl (-SH) groups of cysteine and glutathione, characterized by high polarizability and low electronegativity (Pearson, R. G., 1963, J. Am. Chem. Soc.). These nucleophiles are vital for cellular homeostasis, participating in redox signaling, enzymatic catalysis, and the detoxification of electrophilic xenobiotics (Forman, H. J., et al., 2009, Mol. Aspects Med.). In pharmacology, they are the primary sites for covalent drug attachment; for instance, targeted covalent inhibitors (TCIs) like ibrutinib form bonds with specific cysteine residues to inhibit kinase activity (Singh, J., et al., 2011, Nat. Rev. Drug Discov.). However, the high reactivity of these groups also poses toxicological risks, as non-specific electrophilic attack can deplete glutathione or form immunogenic protein adducts (Liebler, D. C., 2008, Chem. Res. Toxicol.). Consequently, while they are essential for drug efficacy in certain contexts, they also represent a major pathway for drug-induced toxicity and off-target effects.

Other names

Biological thiolsSulfhydryl groupsCysteine residuesGlutathioneSoft nucleophilic centers

Covalent modification of nucleophilic residues (primarily cysteine) via Michael addition or nucleophilic substitution to inhibit enzyme activity or modulate cellular redox state.