Structure-Based Discovery of Substituted 4,5′-Bithiazoles as Novel DNA Gyrase Inhibitors
Structure-Based Discovery of Substituted 4,5′-Bithiazoles as Novel DNA Gyrase Inhibitors
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DOI：
10.1021/jm300395d
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发表时间：
2012-07-26
影响因子：
7.3
通讯作者：
Solmajer, Tom
中科院分区：
文献类型：
--
作者：
Brvar, Matjaz;Perdih, Andrej;Solmajer, Tom
细菌DNA旋切酶是开发新型抗菌药物的有效靶点。从现有的关于天然产物抑制剂氯生素结合的结构信息出发，我们通过实施两步结构设计程序，鉴定了一系列具有低微摩尔抑制活性的4'-甲基- n -2-苯基-[4,5'-双噻唑]-2,2'-二胺抑制剂。这种新型的DNA回转酶抑制剂通过各种技术（差示扫描荧光法，表面等离子体共振和微尺度热电泳）进行了广泛的研究。x射线晶体学揭示了强效抑制剂18的结合模式，证实了我们最初的硅结合模型。此外，高分辨率的复合物结构允许放置Gly97-Ser108柔性环，从而揭示了其在这类化合物结合中的作用。复合物蛋白G24和抑制剂18的晶体结构为进一步优化这类新型DNA回转酶B抑制剂提供了有价值的信息。
Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N-2-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.