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Substrate-based discovery of α-hydroxycarboxylic acid derivatives as potential herbicides targeting dihydroxyacid dehydratase

Author

Listed:
  • Bo He

    (Nanjing Agricultural University)

  • Yanhao Hu

    (Nanjing Agricultural University)

  • Dongshan Liu

    (Chinese Academy of Science)

  • Xin Zang

    (Chinese Academy of Science)

  • Xu He

    (Nanjing Agricultural University)

  • Wang Chen

    (Nanjing Agricultural University)

  • Jingfang Yang

    (Chinese Academy of Agricultural Sciences)

  • Mingfeng Feng

    (Nanjing Agricultural University)

  • Ping Chen

    (Nanjing Agricultural University)

  • Lirong Wei

    (Nanjing Agricultural University)

  • Yu Li

    (Nanjing Agricultural University)

  • Wei Yan

    (Nanjing Agricultural University)

  • Jun Li

    (Nanjing Agricultural University)

  • Zhike Feng

    (Nanjing Agricultural University)

  • Jiahai Zhou

    (Chinese Academy of Science
    Nanjing Normal University)

  • Yonghao Ye

    (Nanjing Agricultural University)

Abstract

Dihydroxyacid dehydratase (DHAD), a key enzyme in branched-chain amino acid synthesis in plants, is a promising yet unexploited herbicide target. Inspired by the natural DHAD inhibitor aspterric acid, we design benzoxazinone derivatives with α-hydroxycarboxylic acid moieties as potential inhibitors and develop an eco-friendly α-C(sp³)-H hydroxylation method for accessing carbonyl compounds. Among the derivatives, 7-fluoro-2-hydroxy-3-oxo-4-propyne-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (I-6e) completely inhibits Arabidopsis thaliana germination and suppress six weed species by > 50%, with 100% efficacy against Avena fatua and Setaria viridis at 150 g ai/ha. This broad-spectrum activity and rice crop safety highlight its potential as an herbicide lead compound. Compound I-6e exhibits stronger affinity for DHAD (Kd = 1 µM) than that of the natural substrate (Kd = 5.39 µM). The 2.19 Å cocrystal structure of the AtDHAD–I-6e complex reveals a unique binding mechanism, confirming the critical role of the α-hydroxycarboxylic acid scaffold. This study provides a blueprint for rational DHAD inhibitor design.

Suggested Citation

  • Bo He & Yanhao Hu & Dongshan Liu & Xin Zang & Xu He & Wang Chen & Jingfang Yang & Mingfeng Feng & Ping Chen & Lirong Wei & Yu Li & Wei Yan & Jun Li & Zhike Feng & Jiahai Zhou & Yonghao Ye, 2025. "Substrate-based discovery of α-hydroxycarboxylic acid derivatives as potential herbicides targeting dihydroxyacid dehydratase," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60489-8
    DOI: 10.1038/s41467-025-60489-8
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    References listed on IDEAS

    as
    1. Thierry Lonhienne & Yan Cheng & Mario D. Garcia & Shu Hong Hu & Yu Shang Low & Gerhard Schenk & Craig M. Williams & Luke W. Guddat, 2022. "Structural basis of resistance to herbicides that target acetohydroxyacid synthase," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Joanne L. Parker & Simon Newstead, 2014. "Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1," Nature, Nature, vol. 507(7490), pages 68-72, March.
    3. Yan Yan & Qikun Liu & Xin Zang & Shuguang Yuan & Undramaa Bat-Erdene & Calvin Nguyen & Jianhua Gan & Jiahai Zhou & Steven E. Jacobsen & Yi Tang, 2018. "Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action," Nature, Nature, vol. 559(7714), pages 415-418, July.
    4. Anastasiia V. Sadybekov & Vsevolod Katritch, 2023. "Computational approaches streamlining drug discovery," Nature, Nature, vol. 616(7958), pages 673-685, April.
    5. Thierry Lonhienne & Yu Shang Low & Mario D. Garcia & Tristan Croll & Yan Gao & Quan Wang & Lou Brillault & Craig M. Williams & James A. Fraser & Ross P. McGeary & Nicholas P. West & Michael J. Landsbe, 2020. "Structures of fungal and plant acetohydroxyacid synthases," Nature, Nature, vol. 586(7828), pages 317-321, October.
    6. Michael J. Jaroszewicz & Mengxiao Liu & Jihyun Kim & Guannan Zhang & Yaewon Kim & Christian Hilty & Lucio Frydman, 2022. "Time- and site-resolved kinetic NMR for real-time monitoring of off-equilibrium reactions by 2D spectrotemporal correlations," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
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