Discovery of a species‐specific novel antifungal compound against Fusarium graminearum through an integrated molecular modeling strategy

Abstract

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 fungus Fusarium graminearum worldwide. 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 of F. graminearum, but not against other fungal species. Moreover, 10 also inhibits conidial germination of phenamacril-resistant strains effectively. Further experiments illustrated that application of 10 could dramatically inhibit deoxynivalenol biosynthesis. CONCLUSION: Overall, our results further optimize and develop the binding model of phenamacril-myosin I. Furthermore, 10 was found and has the potential to be developed as a species-specific fungicide for management of FHB.

Future direction of agrochemical development for plant disease in China

“…In addition, there are also some potential targets for the drug design. Using FgMyo1 inhibitor as a potential target, Fu et al (2020) combined molecular modeling strategies among homology modeling, molecular docking, molecular dynamics (MD) simulations, and variable dielectric molecular mechanics to obtain a novel phenamacril derivative, a species-specific novel antifungal compound, which showed higher activity than that of phenamacril against conidial germination of Fusarium graminearum. Moreover, there are also other studies targeting some enzymes such as the cytochrome P450-dependent sterol 14α-demethylase, to design antifungal molecules (Chen et al, 2018).…”

Discovery of a Novel Fusarium Graminearum Mitogen-Activated Protein Kinase (FgGpmk1) Inhibitor for the Treatment of Fusarium Head Blight

“…That model was successfully used in the discovery of a potent compound against F. graminearum . In this study, the VD-MM/GBSA was employed to predict the binding free energies of 21 and 94 to FgGpmk1.…”

“…45 That model was successfully used in the discovery of a potent compound against F. graminearum. 46 In this study, the VD-MM/GBSA was employed to predict the binding free energies of 21 and 94 to FgGpmk1. A total of 500 snapshots for each system were extracted from the CMD simulations trajectories of 250− 300 ns, and the other parameters were the same as those used in the previous studies.…”

“…A total of 500 snapshots for each system were extracted from the CMD simulations trajectories of 250− 300 ns, and the other parameters were the same as those used in the previous studies. 45,46 GaMD Simulations of the FgGpmk1−94 Complex. The initial structure for the GaMD simulations was extracted from the equilibrated structures of CMD simulations.…”

VAD-MM/GBSA: A Variable Atomic Dielectric MM/GBSA Model for Improved Accuracy in Protein–Ligand Binding Free Energy Calculations

“…Inspiringly, this model had been successfully applied in the discovery of novel androgen receptor antagonists for the development of prostate cancer therapeutics 23 and identification of a novel antifungal compound against Fusarium graminearum. 24 Although GB models have achieved some improvements, it should be noted that the dielectric constants of the same type residues should be different in the different regions of one protein (such as in the core and on the surface) or in different proteins with different physicochemical environments. Hence, various plausibly rigorous computational methods had been developed by considering the distance, geometry, charge, and other parameters to assign dielectric constants to atoms included in protein/ligand binding cavities.…”