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

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

  • J Agric Food Chem. 2025 Jul 2;73(26):16147-16156. doi: 10.1021/acs.jafc.5c03093.
Kun Li 1 2,  Jia Li 1 2,  Zhenwu Yu 1 2 3,  Rongzhang Wu 1 2,  Shishuo He 1 2,  Yaru Sun 1 2,  Taixiang Chen 1 2,  Yiheng Zhang 1 2,  Liangfu Tang 1 2,  Zhijin Fan 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
  • 2 Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
  • 3 College of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
PMID: 40522221 DOI: 10.1021/acs.jafc.5c03093
Abstract

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.

Keywords

3D-QSAR; Rhizoctonia solani; SDH; design and synthesize; fungicide.

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