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Related Experiment Video

Updated: Sep 7, 2025

Screening Traditional Chinese Medicine Compounds for Inhibiting UCHL3 Activity Based on Molecular Docking and Deubiquitinating Enzyme Probe Technology
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Virtual screening based on pharmacophore model for developing novel HPPD inhibitors.

Jia-Yu Wang1, Shuang Gao1, Juan Shi1

  • 1Department of Chemistry, College of Arts and Sciences, Northeast Agricultural University, Harbin 150030, China.

Pesticide Biochemistry and Physiology
|June 17, 2022
PubMed
Summary

Researchers identified novel small-molecule inhibitors for 4-hydroxyphenylpyruvate dioxygenase (HPPD) using computational methods. Compound-139 shows potent herbicidal activity, while compound-5222 inhibits human HPPD.

Keywords:
Activity verificationHPPD inhibitorMolecular dockingMolecular dynamicsPharmacophore model

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Area of Science:

  • Biochemistry
  • Computational Chemistry
  • Agrochemistry

Background:

  • 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme and a significant target for developing effective herbicides.
  • Existing herbicides targeting HPPD face challenges related to resistance and selectivity.
  • Novel small-molecule inhibitors are needed to overcome these limitations and improve weed management strategies.

Purpose of the Study:

  • To identify novel small-molecule inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD) using a comprehensive in silico screening approach.
  • To evaluate the binding interactions and potential efficacy of identified compounds against plant and human HPPD.
  • To provide insights for the rational design of new HPPD-inhibiting herbicides.

Main Methods:

  • A multilayered virtual screening workflow combining pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations.
  • Screening of approximately 110,000 compounds from Bailingwei and traditional Chinese medicine databases.
  • In vitro enzyme activity assays to determine inhibitory potency (IC50) against Arabidopsis thaliana HPPD (AtHPPD) and human HPPD.
  • Assessment of herbicidal activity of lead compounds against gramineous weeds.

Main Results:

  • A total of 333 compounds were analyzed via docking, with five selected based on binding patterns and interactions with the active site.
  • All selected compounds formed stable coordination with cobalt ions and exhibited favorable pi-pi interactions.
  • Molecular dynamics simulations highlighted the significant binding contributions of Phe381 and Phe424.
  • Compound-139 demonstrated potent inhibition of AtHPPD (IC50 = 0.742 μM) and exhibited herbicidal activity.
  • Compound-5222 showed significant inhibition of human HPPD (IC50 = 6 nM).

Conclusions:

  • The integrated in silico approach successfully identified potential HPPD inhibitors.
  • Compound-139 represents a promising candidate for herbicide development due to its potent AtHPPD inhibition and herbicidal activity.
  • Compound-5222's inhibition of human HPPD warrants further investigation regarding potential off-target effects.
  • This study provides valuable insights for the future design of novel HPPD inhibitors through computational techniques.