title: Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery.
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.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Hallenbeck
authors.forename: David M
authors.initials: DM
authors.lastname: Turner
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, Box 2552, San Francisco, CA 94158, USA. michelle.arkin@ucsf.edu.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
mesh_terms: D002384:Catalysis; D003545:Cysteine / Q000737:chemistry*; D055808:Drug Discovery; D015394:Molecular Structure
chemical_list: D003545:Cysteine