Succinate dehydrogenase inhibitors for fusarium head blight control

Overview

Fusarium head blight (FHB) is a destructive crop disease caused by Fusarium graminearum that threatens cereal grain yields and quality worldwide. This solution presents two computationally identified active compounds from the milbemycin class (phenylpropanoid and polyketoid superclass) that potently bind and stabilize the succinate dehydrogenase (SDH) enzyme of Fusarium graminearum. By blocking fungal respiration through SDH inhibition, these actives offer a promising route to controlling FHB. The identified compounds also display anti-bacterial properties, broadening their potential utility across crop protection and antimicrobial applications.

Technical specifications

Discovery approach:

• High-throughput virtual screening of 512 candidate insecticide molecules sourced from the FungiPAD database
• 3D AlphaFold structure (AF-T1QD46-F1) of Fusarium graminearum succinate dehydrogenase was retrieved and stabilized through 50 nanosecond molecular dynamics simulation
• Active site residues were identified and used for molecular docking of all 512 candidates in their best-fit orientations
• Schrödinger docking results narrowed the pool to the top ten binders, followed by 100 nanosecond molecular dynamics simulations to assess binding stability
• Two lead actives belonging to macrolides and analogues (milbemycin sub-class) emerged as the most potent and stable binders

Key features:

• Targets the SDH respiration pathway essential to Fusarium survival
• Dual anti-fungal and anti-bacterial activity in the identified leads
• Novel mode of action that differentiates these actives from existing fungicide chemistries
• Computational evidence of strong, stable binding to the target enzyme

Technology readiness level

The research is currently at the computational validation stage. Lead actives have been identified through structure-based virtual screening and molecular dynamics simulations confirming stable enzyme binding. The next step is in vitro testing to confirm fungicidal efficacy against FHB, followed by investigation of metabolic pathways to fully characterize the new mode of action. The work is ready to progress into laboratory validation and would benefit from partners with capabilities in antifungal assay development, formulation chemistry, and agricultural field testing.