强效乙硫酰胺助推器的结构与对接研究。

IF 0.8 4区 化学 Acta crystallographica. Section C, Crystal structure communications Pub Date : 2013-11-01 Epub Date: 2013-10-24 DOI:10.1107/S0108270113028126
Natalie J Tatum, Baptiste Villemagne, Nicolas Willand, Benoit Deprez, John W Liebeschuetz, Alain R Baulard, Ehmke Pohl
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引用次数: 11

摘要

结核病仍然是全世界仅次于艾滋病毒的第二大传染病死亡原因,2011年在全球造成140万人死亡。二线抗结核方案的基本药物之一是20世纪60年代推出的前药乙硫胺。乙硫胺主要用于因严重不良副作用而导致的耐多药和广泛耐药结核病病例。作为前药,乙硫酰胺被EthA生物激活,EthA是一种单加氧酶,其活性被EthR抑制,EthR是TetR调节家族的成员。先前的研究已经证实,抑制乙烷受体可以提高乙酰胺的效力。我们报告三个EthR抑制剂的晶体结构为0.8一项决议(3-oxo-3 - {4 - [3 - (thiophen-2-yl) 1、2、4-oxadiazol-5-yl] piperidin-1-yl} propanenitrile (BDM31343), 4, 4, 4-trifluoro-1 - {4 - [3 - (6-methoxy-1 3-benzothiazol-2-yl) 1、2,4-oxadiazol-5-yl] piperidin-1-yl}丁酮(BDM41325)和5 5 5-trifluoro-1 - {4 - [3 - (4-methanesulfonylphenyl) 1、2、4-oxadiazol-5-yl] piperidin-1-yl}戊酮(BDM41907)),和对接研究进行调查可能绑定模式。结果显示,这三种化合物在结合通道中有两种不同的取向,这是主要亲脂性结合位点混杂性质的直接结果。
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Structural and docking studies of potent ethionamide boosters.

Tuberculosis remains the second only to HIV as the leading cause of death by infectious disease worldwide, and was responsible for 1.4 million deaths globally in 2011. One of the essential drugs of the second-line antitubercular regimen is the prodrug ethionamide, introduced in the 1960s. Ethionamide is primarily used in cases of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB due to severe adverse side effects. As a prodrug, ethionamide is bioactivated by EthA, a mono-oxygenase whose activity is repressed by EthR, a member of the TetR family of regulators. Previous studies have established that inhibition of EthR improves ethionamide potency. We report here the crystal structures of three EthR inhibitors at 0.8 Å resolution (3-oxo-3-{4-[3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}propanenitrile (BDM31343), 4,4,4-trifluoro-1-{4-[3-(6-methoxy-1,3-benzothiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}butanone (BDM41325) and 5,5,5-trifluoro-1-{4-[3-(4-methanesulfonylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pentanone (BDM41907)), and the docking studies undertaken to investigate possible binding modes. The results revealed two distinct orientations of the three compounds in the binding channel, a direct consequence of the promiscuous nature of the largely lipophilic binding site.

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期刊介绍: Acta Crystallographica Section C: Structural Chemistry is continuing its transition to a journal that publishes exciting science with structural content, in particular, important results relating to the chemical sciences. Section C is the journal of choice for the rapid publication of articles that highlight interesting research facilitated by the determination, calculation or analysis of structures of any type, other than macromolecular structures. Articles that emphasize the science and the outcomes that were enabled by the study are particularly welcomed. Authors are encouraged to include mainstream science in their papers, thereby producing manuscripts that are substantial scientific well-rounded contributions that appeal to a broad community of readers and increase the profile of the authors.
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Equilin. (+-)-Tartaric acid. DL-Proline. DL-Alanine. The Etymology of Chemical Names. Tradition and Convenience vs. Rationality in Chemical Nomenclature. By Alexander Senning. De Gruyter, 2019. Hardcover, Pp. xiv+505. Price EUR 149.95, USD 172.99, GBP 136.50. ISBN 978-3-11-061106-9.
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