Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.
Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.
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DOI：
10.1038/srep27792
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发表时间：
2016-06-10
影响因子：
4.6
通讯作者：
Ekins S
中科院分区：
文献类型：
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作者：
Djaout K;Singh V;Boum Y;Katawera V;Becker HF;Bush NG;Hearnshaw SJ;Pritchard JE;Bourbon P;Madrid PB;Maxwell A;Mizrahi V;Myllykallio H;Ekins S
目前迫切需要为结核病找到新的治疗方法，这是一种由结核分枝杆菌引起的主要传染病，每年导致150万人死亡。我们已经瞄准了这种有机体中的两种关键酶，它们有望用于抗菌治疗，据报道，它们可以被萘醌类化合物抑制。ThyX是一种必需的胸苷合成酶，在机制和结构上与人类的酶无关。DNA旋转酶是一种DNA拓扑异构酶，存在于细菌和植物中，而不存在于动物中。本研究采用化学信息学和体外筛选相结合的方法，试图了解结核分枝杆菌中这些靶点的构效关系。在这里，我们报告了新的结核分枝杆菌ThyX抑制剂2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1，4-dihydronaphthalene-1，4-dione)和艾地苯酮的鉴定，它们显示出适度的全细胞活性，似乎至少部分地通过靶向结核分枝杆菌的ThyX发挥作用。
There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb.