3D-QSAR-Guided Molecule Design and Protein-Ligand Interaction Studies for Discovery of Succinate Dehydrogenase...

Succinate dehydrogenase (SDH) is an ideal fungicidal target. Here, a three-dimensional quantitative structure-activity relationship (3D-QSAR) was established based on the data of 74 compounds with activity against Rhizoctonia solani. By integrating our previously reported 3D-QSAR findings with the current model, a series of pyrazole-containing compounds were rationally designed and synthesized. Bioassay results demonstrated that B5, with an EC₅₀ of 0.002 μg/mL against R. solani, outperformed fluxapyroxad (0.01 μg/mL). Enzyme activity assays revealed that the IC₅₀ of B5 was 0.12 μM, significantly better than that of fluxapyroxad (0.35 μM). The in vivo fungicidal activity of B5 was 94.44% at 200 μg/mL, which was comparable to that of fluxapyroxad (88.89%). Transcriptomic analysis indicated that B5 affects the tricarboxylic acid cycle, sharing the same mode of action as the traditional succinate dehydrogenase inhibitors. Molecular docking and molecular dynamics simulations revealed that the binding modes of B5 were strongly correlated to its potent antifungal activity. Notably, B5, a lead compound without a thiazole substructure, is worthy of further investigation.