Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery.
Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery.
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DOI：
10.2174/1568026616666160719163839
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发表时间：
2017
影响因子：
3.4
通讯作者：
Arkin MR
中科院分区：
文献类型：
--
作者：
Hallenbeck KK;Turner DM;Renslo AR;Arkin MR
利用小分子靶向非催化半胱氨酸残基正引起药物发现科学家和化学生物学家越来越多的关注。从生物学的角度来看，基因组和蛋白质组学研究揭示了几种致癌蛋白中存在半胱氨酸突变，这表明这些残基既具有功能作用，又有一种以“等位基因特异性”的方式靶向它们的策略。对于药物化学家来说，半胱氨酸活性分子的结构导向设计是实现药物先导选择性和药效学性质改善的一种有吸引力的策略。最后，对于化学生物学家来说，半胱氨酸残基的修饰为探索蛋白质结构和变构调节提供了独特的手段。在这里，我们综述了半胱氨酸修饰小分子的三个应用：1)现有药物前导的优化，2)新先导化合物的发现，3)半胱氨酸反应小分子作为蛋白质动力学探针的使用。在每种情况下，结构导向设计在确定目标半胱氨酸残基(S)以及设计具有适当几何结构的化合物以实现与目标半胱氨酸的共价相互作用以及与附近蛋白质残基的有效非共价相互作用方面发挥着关键作用。
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.