Despite years of use as commercial herbicides, it is still unclear how dinitroanilines interact with tubulin, how they cause microtubule disassembly, and why they are selectively active against plant and protozoan tubulin. In this work, through a series of computational studies, a common binding site of oryzalin, trifluralin, and GB-II-5 on apicomplexan and kinetoplastid alpha-tubulin is proposed. Furthermore, to investigate how dinitroanilines affect tubulin dynamics, molecular dynamics simulations of Leishmania alpha-tubulin with and without a bound dinitroaniline are performed. The results obtained provide insight into the molecular mechanism by which these compounds interact with tubulin and function to prevent microtubule assembly. Finally, to aid in the design of effective parasitic microtubule inhibitors, several novel dinitroaniline analogues are evaluated. The location of the binding site and the relative binding affinities of the dinitroanilines all agree well with experimental data.

译文

尽管已作为商业除草剂使用多年,但仍不清楚二硝基苯胺如何与微管蛋白相互作用,它们如何引起微管分解,以及为什么它们对植物和原生动物的微管蛋白具有选择性活性。在这项工作中,通过一系列计算研究,提出了米唑林,三氟拉林和GB-II-5在apicomplexan和动质体 α-微管蛋白上的共同结合位点。此外,为了研究二硝基苯胺如何影响微管蛋白动力学,对有和没有结合的二硝基苯胺的利什曼原虫 α-微管蛋白进行了分子动力学模拟。获得的结果提供了对这些化合物与微管蛋白相互作用并阻止微管组装的分子机制的深入了解。最后,为了帮助设计有效的寄生微管抑制剂,评估了几种新型的二硝基苯胺类似物。结合位点的位置和二硝基苯胺的相对结合亲和力都与实验数据吻合良好。

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