Structure-Based Discovery of Substituted 4,5鈥?Bithiazoles as Novel DNA Gyrase Inhibitors

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• 作者：Matja啪 Brvar ; Andrej Perdih ; Miha Renko ; Gregor Anderluh ; Du拧an Turk ; Tom Solmajer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6413-6426
• 全文大小：665K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

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鈥?methyl-N²-phenyl-[4,5鈥?bithiazole]-2,2鈥?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鈥揝er108 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.