College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Zhejiang Research Institute of Chemical Industry, Hangzhou, China.
Pest Manag Sci. 2020 Dec;76(12):3990-3999. doi: 10.1002/ps.5948. Epub 2020 Jul 8.
The cyanoacrylate fungicide phenamacril targeting fungal myosin I has been widely used for controlling Fusarium head blight (FHB) of wheat caused by the pathogenic fungus Fusarium graminearum worldwide. Therefore, there is great interest in the discovery and development of novel FgMyo1 inhibitors through structure-based drug design for the treatment of FHB.
In this study, the binding mechanism of phenamacril with FgMyo1 was predicted by an integrated molecular modeling strategy. The predicted key phenamacril-binding residues of FgMyo1 were further experimentally validated by point mutagenesis and phenamacril sensitivity assessment. Four novel key residues responsible for phenamacril binding were identified, highlighting the reliability of the theoretical predictions. The subsequent optimization of phenamacril derivatives led to the discovery of a novel compound (10) which shows better activity than phenamacril against conidial germination of F. graminearum, but not against other fungal species. Moreover, 10 also inhibits conidial germination of phenamacril-resistant strains effectively. Further experiments illustrated that application of 10 could dramatically inhibit deoxynivalenol biosynthesis.
Overall, our results further optimize and develop the binding model of phenamacril-myosin I. Furthermore, 10 was found and has the potential to be developed as a species-specific fungicide for management of FHB. © 2020 Society of Chemical Industry.
杀真菌剂氰基丙烯酸酯 phenamacril 靶向真菌肌球蛋白 I，已被广泛用于控制由致病真菌禾谷镰刀菌引起的小麦赤霉病（FHB）。因此，通过基于结构的药物设计发现和开发新型 FgMyo1 抑制剂以治疗 FHB 引起了极大的关注。
在这项研究中，通过整合的分子建模策略预测了 phenamacril 与 FgMyo1 的结合机制。通过定点突变和 phenamacril 敏感性评估进一步实验验证了预测的 FgMyo1 的关键 phenamacril 结合残基。确定了四个负责 phenamacril 结合的新关键残基，突出了理论预测的可靠性。随后对 phenamacril 衍生物进行了优化，发现了一种新型化合物（10），其对禾谷镰刀菌分生孢子萌发的活性优于 phenamacril，但对其他真菌种无活性。此外，10 还能有效抑制 phenamacril 抗性菌株的分生孢子萌发。进一步的实验表明，10 的应用可显著抑制脱氧雪腐镰刀菌烯醇的生物合成。
总体而言，我们的结果进一步优化和开发了 phenamacril-肌球蛋白 I 的结合模型。此外，发现了 10 并具有作为防治 FHB 的特异性杀菌剂开发的潜力。© 2020 化学工业协会。
