Natural phenolic inhibitors of trichothecene biosynthesis by the wheat fungal pathogen Fusarium culmorum: a computational insight into the structure-activity relationship

A model of the trichodiene synthase (TRI5) of the wheat fungal pathogen and type-B trichothecene producerFusarium culmorumwas developed based on homology modelling with the crystallized protein ofF. sporotrichioides. Eight phenolic molecules, namely ferulic acid1, apocynin2, propyl gallate3, eugenol4, Me-dehydrozingerone5, eugenol dimer6, magnolol7, and ellagic acid8, were selected for their ability to inhibit trichothecene production and/or fungal vegetative growth inF. culmorum. The chemical structures of phenols were constructed and partially optimised based on Molecular Mechanics (MM) studies and energy minimisation by Density Functional Theory (DFT). Docking analysis of the phenolic molecules was run on the 3D model ofF. culmorumTRI5. Experimental biological activity, molecular descriptors and interacting-structures obtained from computational analysis were compared. Besides the catalytic domain, three privileged sites in the interaction with the inhibitory molecules were identified on the protein surface. The TRI5-ligand interactions highlighted in this study represent a powerful tool to the identification of newFusarium-targeted molecules with potential as trichothecene inhibitors.