Cellular proteins with nucleophilic residues

Cellular proteins with nucleophilic residues represent a broad class of biological molecules characterized by the presence of reactive amino acid side chains, such as the thiol group of cysteine or the hydroxyl group of serine [1]. These residues are essential for various biological functions, including enzymatic catalysis, where they often act as the primary nucleophile in the active site to facilitate chemical transformations [2]. In the context of pharmacology, these proteins are the primary targets for covalent inhibitors, which utilize electrophilic functional groups to form stable chemical bonds with the nucleophilic residues [3]. This interaction often results in the irreversible inhibition of the protein's activity, providing a prolonged therapeutic effect that is independent of the drug's systemic half-life [1]. While this approach has been highly successful in treating conditions like cancer, inflammation, and bacterial infections, it also poses risks such as off-target reactivity and potential immunogenicity due to the formation of protein-drug adducts [4]. Modern drug discovery efforts focus on designing targeted covalent inhibitors (TCIs) that combine high structural complementarity for a specific protein pocket with a finely tuned electrophilic "warhead" to minimize non-specific reactions [2][3]. These targets span multiple protein families, including kinases like Bruton's tyrosine kinase and proteases like the main protease of SARS-CoV-2, highlighting their diverse roles in human disease and therapy [1][4].

Other names

Nucleophilic protein targetsCovalent drug targetsElectrophile-responsive proteinsReactive residue-containing proteins

Covalent modification of nucleophilic amino acid side chains (e.g., cysteine thiol, serine hydroxyl, lysine amine) by electrophilic drug moieties, resulting in irreversible or slowly reversible modulation of protein function [1][3].