Structure-guided design of antibacterials that allosterically inhibit DNA gyrase
Structure-guided design of antibacterials that allosterically inhibit DNA gyrase
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DOI：
10.1016/j.bmcl.2019.03.029
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发表时间：
2019-06-01
影响因子：
2.7
通讯作者：
Stavenger, Robert A.
中科院分区：
文献类型：
--
作者：
Thalji, Reema K.;Raha, Kaushik;Stavenger, Robert A.
基于母体噻吩支架的X射线结构设计了一系列DNA旋转酶抑制剂，目的是提高生化和全细胞抗菌活性，同时降低心脏离子通道活性。一系列的结合模式和总体设计假设通过与DNA旋转酶的共晶结构得到证实。虽然一些类似物同时保留了生化活性和全细胞抗菌活性，但我们无法显着提高该系列的活性，并且类似物保留了针对心脏离子通道的活性，因此我们停止了优化工作。
A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.