Discovery of a species-specific novel antifungal compound againstFusarium graminearumthrough an integrated molecular modeling strategy

BACKGROUND The cyanoacrylate fungicide phenamacril targeting fungal myosin I has been widely used for controlling Fusarium head blight (FHB) of wheat caused by the pathogenic fungusFusarium graminearumworldwide. Therefore, there is great interest in the discovery and development of novel FgMyo1 inhibitors through structure-based drug design for the treatment of FHB. RESULTS In this study, the binding mechanism of phenamacril with FgMyo1 was predicted by an integrated molecular modeling strategy. The predicted key phenamacril-binding residues of FgMyo1 were further experimentally validated by point mutagenesis and phenamacril sensitivity assessment. Four novel key residues responsible for phenamacril binding were identified, highlighting the reliability of the theoretical predictions. The subsequent optimization of phenamacril derivatives led to the discovery of a novel compound (10) which shows better activity than phenamacril against conidial germination ofF. graminearum, but not against other fungal species. Moreover,10also inhibits conidial germination of phenamacril-resistant strains effectively. Further experiments illustrated that application of10could dramatically inhibit deoxynivalenol biosynthesis. CONCLUSION Overall, our results further optimize and develop the binding model of phenamacril-myosin I. Furthermore,10was found and has the potential to be developed as a species-specific fungicide for management of FHB.