Other cellular proteins with nucleophilic residues

Other cellular proteins with nucleophilic residues is a descriptive category rather than a specific biological target. It encompasses a wide variety of proteins that possess reactive functional groups, such as the thiol group of cysteine or the amino group of lysine, which can react with electrophilic molecules (Sutcliffe et al., 2011, PMC3136715). In pharmacology, this term is frequently used to describe the sites of off-target covalent binding for drugs designed as covalent inhibitors (Singh et al., 2011, Nature Reviews Drug Discovery). While the primary therapeutic effect of such drugs comes from binding to a specific protein, non-selective interaction with these other proteins can lead to the formation of protein-drug adducts (Liebler, 2008, Chemical Research in Toxicology). These adducts are often associated with toxicological outcomes, including cellular dysfunction and the induction of immune responses (Park et al., 2005, PubMed 15922018). Specifically, the modification of off-target proteins can create haptens that trigger idiosyncratic drug reactions, posing a significant challenge for drug safety (Uetrecht, 2007, PubMed 17907110). Therefore, characterizing these nucleophilic residues is essential for minimizing toxicity during the development of electrophilic medicinal chemistry.

Other names

Nucleophilic protein residuesCovalent off-targetsReactive protein side chainsNucleophilic amino acid residues

Covalent modification of nucleophilic amino acid side chains (e.g., cysteine, lysine, serine) via electrophilic attack, resulting in the formation of stable protein-drug adducts.