Details

Autor(en) / Beteiligte

• Hallenbeck, Kenneth K
• Turner, David M
• Renslo, Adam R
• Arkin, Michelle R

Titel

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

Ist Teil von

• Current topics in medicinal chemistry, 2017-01, Vol.17 (1), p.4-15

Ort / Verlag

United Arab Emirates

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.