Discovery of a Fungicide Candidate Targeting Succinate Dehydrogenase via Computational Substitution Optimization
Discovery of a Fungicide Candidate Targeting Succinate Dehydrogenase via Computational Substitution Optimization
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通过计算替换优化发现针对琥珀酸脱氢酶的候选杀菌剂
DOI：
10.1021/acs.jafc.1c04536
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发表时间：
2021-10-28
影响因子：
6.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Li, Hua;Wang, Yu-Xia;Yang, Guang-Fu
琥珀酸脱氢酶（SDH，EC 1.3.5.1）已被证明是重要的杀真菌靶标，并且SDH的抑制在植物病原体的处理中是有用的。发现一种新的活性SDH抑制剂具有很高的价值。在此，我们公开了通过使用计算取代优化方法（在我们实验室开发的快速药物设计方法）发现作为杀真菌剂候选物的有效的、高活性的抑制剂。温室盆栽试验结果表明，化合物17 c在0.781 mg/L的低剂量下对玉米锈病、大豆锈病和水稻纹枯病均有较好的防治效果。此外，田间试验表明，化合物17 c在50 mg/L浓度下对SBR和黄瓜白粉病的抑制效果与市售杀菌剂相当甚至更好。最令人惊讶的是，化合物17 c的治疗活性严格优于商业杀真菌剂苯并烯氟吡菌。计算结果表明，17 c可以与C_S42形成另一个氢键，从而与SDH产生较强的货车范德华力和电子相互作用。结果表明，17 c是一种潜在的SDH杀菌剂候选物。
Succinate dehydrogenase (SDH, EC 1.3.5.1) has proven to be an important fungicidal target, and the inhibition of SDH is useful in the treatment of plant pathogens. The discovery of a novel active SDH inhibitor is of high value. Herein, we disclose the discovery of a potent, highly active inhibitor as a fungicide candidate by using a computational substitution optimization method, a fast drug design method developed in our laboratory. The greenhouse experiments showed that compound 17c exhibited high protective activity against south corn rust, soybean rust (SBR), and rice sheath blight at a very low dosage of 0.781 mg/L. Moreover, the field trials indicated that compound 17c is comparable to and even better than commercial fungicides against SBR and cucumber powdery mildew at 50 mg/L concentration. Most surprisingly, compound 17c resulted to be strictly better in curative activity than the commercial fungicide benzovindiflupyr. The computation results indicated that 17c could form another hydrogen bond with C_S42 and then lead to strong van der Waals and electronic interactions with SDH. Our results suggested that 17c is a potential fungicide candidate for SDH.