Off-target cysteine-containing and non-cysteine proteins

Off-target cysteine-containing and non-cysteine proteins is a collective term used in pharmacology to describe the unintended protein population that interacts with a drug, often leading to adverse effects. This concept is particularly significant for covalent inhibitors, which utilize electrophilic functional groups to form a stable chemical bond with a specific nucleophilic residue, typically a cysteine, on the intended therapeutic target (Singh et al., 2011, Nature Reviews Drug Discovery). However, the human proteome contains a vast number of reactive cysteines, and off-target interactions occur when the drug reacts with these non-intended sites, potentially disrupting essential cellular processes or triggering immune responses (Backus et al., 2016, Nature Chemical Biology). Non-cysteine off-targets involve proteins that bind the drug through non-covalent interactions or react with other residues such as lysine, histidine, or tyrosine. Identifying and minimizing these interactions is a central challenge in drug design to ensure safety and reduce the risk of idiosyncratic drug toxicity (Lonsdale et al., 2017, Chemical Society Reviews). Because this term refers to a broad category of unintended interactions rather than a single therapeutic entity, it is classified as a descriptive grouping of off-targets.

Other names

Off-target proteomeCovalent off-targetsNon-specific protein adductsBystander proteinsReactive metabolite targets

Unintended covalent modification and non-specific binding