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

Author(s): Kenneth K. Hallenbeck, David M. Turner, Adam R. Renslo, Michelle R. Arkin

Journal Name: Current Topics in Medicinal Chemistry

Volume 17 , Issue 1 , 2017

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Graphical Abstract:


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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Article Details

Year: 2017
Published on: 19 July, 2016
Page: [4 - 15]
Pages: 12
DOI: 10.2174/1568026616666160719163839
Price: $65

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