A Novel Dual-Target Compound Designed With Potent Herbicidal and Fungicidal Activity Inspired by Conserved Phytoene...

The development of dual-target inhibitors represents a cost-effective strategy for integrated pest management. Here, we report the first dual-target inhibitors designed against the evolutionarily conserved domain of phytoene synthase (PSY), a key enzyme in carotenoid biosynthesis. Using comparative genomics, we identified structural conservation between PSY in plants and squalene synthase (erg9) in fungi. Through virtual screening and structure-based optimization of compounds targeting PSY, we identified lead compound 1c, which exhibited potent herbicidal and fungicidal activity. In vitro binding assays confirmed that 1c binds to both PSY and erg9. In plants, 1c treatment reduced chlorophyll content, downregulated photosynthesis-associated genes, and caused substrate accumulation in the carotenoid pathway. In fungi, 1c induced a mycelial morphology identical to erg9 knockout mutants. Molecular dynamics simulations revealed the differential binding conformations of 1c to PSY and erg9, elucidating its mode of action. This work establishes PSY and its homologues as a promising target for the development of novel, broad-spectrum dual-action agrochemicals based on targetome structural similarity.