Herbicide resistance is a major challenge for global agriculture, requiring new modes of action to maintain crop protection. Fatty acid thioesterases (FATs), enzymes that terminate fatty acid biosynthesis in plants, have emerged as promising herbicide targets because they are absent in animals and thus pose low toxicity risks.
In a recent study by Syngenta Crop Protection and the Centre for Medicines Discovery, researchers determined the crystal structure of Arabidopsis thaliana FatA at 1.5 Å resolution and conducted a fragment-based screening campaign using the XChem fragment screening facility at Diamond. The screen identified 129 unique fragments bound in 141 poses, revealing three key binding sites:
- Herbicide binding site: Deep, hydrophobic pocket where most potent fragments bind.
- Active site: Near the surface, interacting with catalytic residues.
- Dimer interface: Potential for allosteric inhibition by disrupting dimerisation.
This study delivers a structural and biophysical platform for rational herbicide design, identifying fragment hits that enable rapid, structure-guided development of novel FAT inhibitors.
These diverse scaffolds overcome current limitations, reduce cross-resistance, and support pharmaceutical-style strategies to accelerate hit-to-lead progression. Dual FatA/FatB targeting remains key, paving the way for innovative herbicides to strengthen global food security.