Ametoctradin is a Potent Q(o) Site Inhibitor of the Mitochondria! Respiration Complex III
Ametoctradin is a Potent Q(o) Site Inhibitor of the Mitochondria! Respiration Complex III
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Ametoctradin 是一种有效的线粒体 Q(o) 位点抑制剂！
DOI：
10.1021/acs.jafc.5b00228
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发表时间：
2015
影响因子：
6.1
通讯作者：
Yang Guangfu
中科院分区：
文献类型：
--
作者：
Zhu Xiaolei;Zhang Mengmeng;Liu Jingjing;Ge Jingming;Yang Guangfu
Ametoctradin是巴斯夫正在开发的一种新型真菌特异性杀菌剂。它是线粒体呼吸中bc1复合物的有效抑制剂。然而，其具体的作用机制尚不清楚。本研究通过分子对接、MD模拟和MM/PBSA计算，首次揭示了ametoctradin的结合模式，表明ametoctradin可能是bc1复合物的aQosite inhibitor。随后，设计并合成了一系列新的1,2,4-三唑[1,5-a]嘧啶衍生物，以进一步了解取代基对1,2,4-三唑[1,5-a]嘧啶5位和6位的影响。新合成的qosite抑制剂类似物的计算结合自由能（ΔGcal）与其实验结合自由能（ΔGexp）具有很好的相关性（R2= 0.96）。成功鉴定出两个对猪SQR具有较高抑制活性的化合物（4a&4c）。从本研究中获得的结构和机制见解将为未来设计新的有希望的bc1抑制剂提供有价值的线索。
Ametoctradin is a newOomycete-specific fungicide under development by BASF. It is a potent inhibitor of thebc1complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be aQosite inhibitor ofbc1complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔGcal) of newly synthesized analogues asQosite inhibitors correlated very well (R2= 0.96) with their experimental binding free energies (ΔGexp). Two compounds (4aand4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promisingbc1inhibitor.