Submit Manuscript  

Article Details

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

[ Vol. 17 , Issue. 1 ]


Kenneth K. Hallenbeck, David M. Turner, Adam R. Renslo and Michelle R. Arkin   Pages 4 - 15 ( 12 )


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.


Non-catalytic cysteine, Covalent drugs, Structure-based design, Chemical probes, disulfide Tethering, Lead optimization, Protein dynamics, Protein allostery.


Department of Pharmaceutical Chemistry, University of California, San Francisco, Box 2552, San Francisco, CA 94158, USA.

Graphical Abstract:

Read Full-Text article