Integrated Virtual Screening and Validation toward Potential HPPD Inhibition Herbicide

Area of Science:

• Agricultural Chemistry
• Biochemistry
• Medicinal Chemistry

Background:

• 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme in plant pigment biosynthesis and a validated herbicide target.
• Existing HPPD inhibitors face challenges related to resistance and crop selectivity.

Purpose of the Study:

• To develop a virtual screening workflow for identifying novel HPPD inhibitors.
• To discover effective and safe HPPD-inhibiting herbicides for agricultural applications.

Main Methods:

• A multistep virtual screening strategy combining CBP models, Hypogen models, and consensus docking (LibDock, Glide, CDOCKER).
• Filtering of ~1 million molecules based on Lipinski's rules and predictive models.
• In vivo biological evaluation and ADMET prediction of promising candidates.

Main Results:

• Identified four potential HPPD inhibitors through virtual screening.
• Compounds III-1 and III-2 demonstrated herbicidal activity comparable to isoxaflutole.
• Compounds III-1 and III-2 exhibited superior safety across multiple crops (wheat, rice, sorghum, maize).
• Compound III showed favorable ADMET predictions.

Conclusions:

• The developed virtual screening workflow effectively identified novel HPPD inhibitors.
• Compounds III-1 and III-2 represent promising candidates for new herbicide development.
• This study provides a foundation for future HPPD inhibitor design and virtual screening efforts.