Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design
Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design
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DOI：
10.1021/jm020230j
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发表时间：
2002-11-07
影响因子：
7.3
通讯作者：
O'Brien, T
中科院分区：
文献类型：
--
作者：
Choong, IC;Lew, W;O'Brien, T
设计，合成和体外活性的一系列有效的和选择性的小分子抑制剂的caspase-3描述。通过延长系留，我们鉴定出一个水杨酸片段对caspase-3的S-4口袋具有结合亲和力。通过x射线晶体学和分子模型分析，合成了具有K-i = 40 nM可逆抑制caspase-3的4。进一步优化鉴定出一系列K-i值在20-50 nM范围内的有效选择性抑制剂。该系列中最有效的化合物之一66b抑制caspase-3，其K-i = 20 nM，对caspase-3的选择性是7种caspase（1、2和4-8）的8-500倍。4和66b的高分辨率x射线共晶结构支持我们的化合物与caspase-3的预测结合模式。
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S-4 pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K-i = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K-i values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K-i = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.