Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 17, Issue 1, Pages 4-15Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568026616666160719163839
Keywords
Non-catalytic cysteine; Covalent drugs; Structure-based design; Chemical probes; disulfide Tethering; Lead optimization; Protein dynamics; Protein allostery
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Funding
- National Science Foundation
- Pfizer Inc.
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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 cysteine-modifying 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.
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