The targeting of non-catalytic cysteine residues with small molecules is
drawing increased attention from drug discovery scientists and chemical biologists.
From a biological perspective, genomic and proteomic studies have revealed the
presence of cysteine mutations in several oncogenic proteins, suggesting both a
functional role for these residues and also a strategy for targeting them in an ‘allele
specific’ manner. For the medicinal chemist, the structure-guided design of cysteine-
reactive molecules is an appealing strategy to realize improved selectivity
and pharmacodynamic properties in drug leads. Finally, for chemical biologists,
the modification of cysteine residues provides a unique means to probe protein
structure and allosteric regulation. Here, we review three applications of cysteinemodifying
small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead
compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each
case, structure-guided design plays a key role in determining which cysteine residue(s) to target and
in designing compounds with the proper geometry to enable both covalent interaction with the targeted
cysteine and productive non-covalent interactions with nearby protein residues.
Keywords: Non-catalytic cysteine, Covalent drugs, Structure-based design, Chemical probes, disulfide Tethering, Lead optimization,
Protein dynamics, Protein allostery.
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