Mitogen-activated protein kinase FgGpmk1 plays vital roles in the development and virulence of Fusarium graminearum (F. graminearum), the causative agent of Fusarium head blight (FHB). However, to date, the druggability of FgGpmk1 still needs verification, and small molecules targeting FgGpmk1 have never been reported. Here, we reported the discovery of a novel inhibitor 94 targeting FgGpmk1. First, a novel hit (compound 21) with an EC₅₀ value of 13.01 μg·mL^–1 against conidial germination of F. graminearum was identified through virtual screening. Then, guided by molecular modeling, compound 94 with an EC₅₀ value of 3.46 μg·mL^–1 was discovered, and it can inhibit the phosphorylation level of FgGpmk1 and influence the nuclear localization of its downstream FgSte12. Moreover, 94 can inhibit deoxynivalenol biosynthesis without any damage to the host. This study reported a group of FgGpmk1 inhibitors with a novel scaffold, which paves the way for the development of potent fungicides to FHB management.

中文翻译：

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发现用于治疗镰刀菌枯萎病的新型禾谷镰刀菌丝裂原活化蛋白激酶 (FgGpmk1) 抑制剂

丝裂原活化蛋白激酶 FgGpmk1 在禾谷镰刀菌( F. graminearum )的发育和毒力中起着至关重要的作用，禾谷镰刀菌是镰刀菌赤霉病 (FHB) 的病原体。然而，迄今为止，FgGpmk1的成药性仍有待验证，靶向FgGpmk1的小分子从未见报道。在这里，我们报告了针对 FgGpmk1的新型抑制剂94的发现。首先，通过虚拟筛选鉴定了针对禾谷镰刀菌分生孢子萌发的EC ₅₀值为13.01 μg·mL ^–1的新型命中（化合物21）。然后，在分子模型的指导下，化合物94的 EC ₅₀3.46 μg·mL ^{–1 的值}被发现，它可以抑制 FgGpmk1 的磷酸化水平并影响其下游 FgSte12 的核定位。此外，94可以抑制脱氧雪腐镰刀菌烯醇的生物合成，而不会对宿主造成任何损害。该研究报告了一组具有新型支架的 FgGpmk1 抑制剂，这为开发用于 FHB 管理的强效杀菌剂铺平了道路。