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

Trichotecene mycotoxins are produced by filamentous fungi belonging to the Fusarium genus and are among the major causes of crop loss in cereals, furthemore, they may cause severe toxicasis in mammals when contaminated grain or their derivative are ingested. In our previous article a collection of natural and natural-like phenols and hydroxylated biphenyls was tested in vitro and significant trichotecene inhibitory activity and fungitoxic effect were detected on F. culmorum over a range of concentrations comprised between 0.25-1.5 mM. Aiming to provide further insight into the understanding of structure-activity relationship of trichothecene inhibitors and TRI5, we have adopted an approach based on modelling techniques. A model of the trichodiene synthase (TRI5) of the wheat fungal pathogen and type-B trichothecene producer F. culmorum was developed based on homology modelling with the crystallized protein of F. sporotrichioides. Eight phenolic molecules were selected for their ability to inhibit trichothecene production and/or fungal vegetative growth in F. culmorum. Experimental biological activity, molecular descriptors and interacting-structures obtained from computational analysis were compared. Besides the catalytic domain, three privileged sites (sites 1, 2 and 4) of the five identified on the protein surface, were evidenced. The TRI5-ligand interactions highlighted in this study represent a powerful tool to the identification of new Fusarium-targeted molecules with potential as trichothecene inhibitors.