Discovery of Potential Fungal Dihydroorotate Dehydrogenase Inhibitors Via Structure-based Virtual Screening for Plant...

Dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway of phytopathogenic fungi, has emerged as a promising target for fungicide discovery. In this study, compound VS-24 was identified from a commercial chemical library using molecular docking-based virtual screening and bioactivity assays. Antifungal tests demonstrated that at a concentration of 50 mg/L, VS-24 has broad-spectrum inhibitory effects with inhibition rates of 96.0%, 76.7%, 75.3%, and 76.5% against Valsa mali, Botrytis cinerea, Gaeumannomyces graminis, and Magnaporthe oryzae, respectively. Furthermore, VS-24 provided 45.1% protection against V. mali on apple branches at a concentration of 200 mg/L. Enzyme inhibition assays confirmed its potent inhibitory activity against DHODH. Molecular docking and dynamics simulations further revealed stable binding interactions between VS-24 and DHODH. This study identifies VS-24 as a valuable hit compound, which provides a foundation for developing novel DHODH inhibitors to control plant fungal diseases.