Generic nucleophilic sites on proteins and biomolecules

Generic nucleophilic sites on proteins and biomolecules refer to electron-rich functional groups, such as the thiol group of cysteine, the epsilon-amino group of lysine, and the imidazole ring of histidine, which are capable of donating an electron pair to electrophiles (Nature Reviews Drug Discovery, 2011, 10, 307-317). These sites are essential for biological processes, including enzymatic catalysis, where they often act as catalytic residues, and post-translational modifications like phosphorylation or acetylation (Biochemistry, 5th Ed, Berg et al.). In a pharmacological context, these sites are the targets of covalent drugs, such as alkylating agents used in oncology (e.g., cyclophosphamide) and targeted covalent inhibitors (TCIs) like ibrutinib (Journal of Medicinal Chemistry, 2015, 58, 13, 5171–5184). While TCIs are designed for specificity, generic nucleophilic reactivity is often associated with non-specific toxicity, as electrophilic compounds can form adducts with a wide array of cellular proteins and DNA (Chemical Research in Toxicology, 2016, 29, 8, 1241–1252). This lack of specificity can lead to adverse effects such as mutagenicity, carcinogenicity, and the formation of haptens that trigger immune responses (Toxicological Sciences, 2012, 127, 1, 1–10). Consequently, while these sites are chemically reactive, they do not constitute a single, discrete therapeutic target but rather a broad class of reactive centers across the proteome.

Other names

Nucleophilic residuesProtein nucleophilesReactive amino acid side chainsBiomolecular nucleophilesNucleophilic centers

Covalent modification through nucleophilic attack on electrophilic drug moieties, leading to the formation of stable adducts.