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 producer Fusarium culmorum was developed based on homology modelling with the crystallized protein of F. sporotrichioides. Eight phenolic molecules, namely ferulic acid 1, apocynin 2, propyl gallate 3, eugenol 4, Me-dehydrozingerone 5, eugenol dimer 6, magnolol 7, and ellagic acid 8, were selected for their ability to inhibit trichothecene production and/or fungal vegetative growth in F. 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 of F. culmorum TRI5. 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 new Fusarium-targeted molecules with potential as trichothecene inhibitors.
Dipartimento di Agraria and Unità di Ricerca Istituto Nazionale di Biostrutture e Biosistemi, Università degli Studi di Sassari, Viale Italia 39, I-07100, Sassari, Italy.
Giovanna
G
Pani
Istituto CNR di Chimica Biomolecolare, Traversa La Crucca 3, I-07100, Sassari, Italy.
Alessandro
A
Dessì
Istituto CNR di Chimica Biomolecolare, Traversa La Crucca 3, I-07100, Sassari, Italy.
Roberto
R
Dallocchio
Dipartimento di Agraria and Unità di Ricerca Istituto Nazionale di Biostrutture e Biosistemi, Università degli Studi di Sassari, Viale Italia 39, I-07100, Sassari, Italy.
Barbara
B
Scherm
Istituto CNR di Chimica Biomolecolare, Traversa La Crucca 3, I-07100, Sassari, Italy.
Emanuela
E
Azara
Istituto CNR di Chimica Biomolecolare, Traversa La Crucca 3, I-07100, Sassari, Italy.
Giovanna
G
Delogu
Dipartimento di Agraria and Unità di Ricerca Istituto Nazionale di Biostrutture e Biosistemi, Università degli Studi di Sassari, Viale Italia 39, I-07100, Sassari, Italy.
Quirico
http://orcid.org/0000-0002-2459-5833
Q
Migheli
D053898:Biosynthetic Pathways / Q000187:drug effects; D019755:Carbon-Carbon Lyases / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D005659:Fungicides, Industrial / Q000737:chemistry / Q000633:toxicity*; D005670:Fusarium / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010636:Phenols / Q000737:chemistry / Q000633:toxicity*; D010935:Plant Diseases / Q000382:microbiology* / Q000517:prevention & control; D013329:Structure-Activity Relationship; D014255:Trichothecenes / Q000378:metabolism*; D014908:Triticum / Q000382:microbiology*
D005656:Fungal Proteins; D005659:Fungicides, Industrial; D010636:Phenols; D014255:Trichothecenes; D019755:Carbon-Carbon Lyases; C051130:trichodiene synthetase