Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase-a potential target to reduce Fusarium head blight disease.
Fusarium head blight (FHB) is one of the most destructive diseases of wheat and other cereals worldwide. During infection, the Fusarium fungi produce mycotoxins that represent a high risk to human and animal health. Developing small-molecule inhibitors to specifically reduce mycotoxin levels would be highly beneficial since current treatments unspecifically target the Fusarium pathogen. Culmorin possesses a well-known important synergistically virulence role among mycotoxins, and longiborneol synthase appears to be a key enzyme for its synthesis, thus making longiborneol synthase a particularly interesting target. This study aims to discover potent and less toxic agrochemicals against FHB. These compounds would hamper culmorin synthesis by inhibiting longiborneol synthase. In order to select starting molecules for further investigation, we have conducted a structure-based virtual screening investigation. A longiborneol synthase structural model is first built using homology modeling, followed by molecular dynamics simulations that provided the required input for a protein-ligand ensemble docking procedure. From this strategy, the three most interesting compounds (hits) were selected among the 25 top-ranked docked compounds from a library of 15,000 drug-like compounds. These putative inhibitors of longiborneol synthase provide a sound starting point for further studies involving molecular modeling coupled to biochemical experiments. This process could eventually lead to the development of novel approaches to reduce mycotoxin contamination in harvested grain.
EMBRAPA Genetic Resources and Biotechnology Parque Estação Biológica - PqEB, Av. W5 Norte, Brasília, DF, Brazil.
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Bresso
CNRS, LORIA, Campus Scientifique, BP 239, 54506, Vandœuvre-lès-Nancy, France.
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Leroux
Department of Plant Biology and Crop Science, Rothamsted Research, Harpenden, Hertfordshire, AL5 2JQ, UK.
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Urban
Department of Plant Biology and Crop Science, Rothamsted Research, Harpenden, Hertfordshire, AL5 2JQ, UK.
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Hammond-Kosack
CNRS, LORIA, Campus Scientifique, BP 239, 54506, Vandœuvre-lès-Nancy, France.
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Maigret
EMBRAPA Genetic Resources and Biotechnology Parque Estação Biológica - PqEB, Av. W5 Norte, Brasília, DF, Brazil. natalia.martins@embrapa.br.
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Martins
D016573:Agrochemicals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D005670:Fusarium / Q000201:enzymology* / Q000378:metabolism / Q000472:pathogenicity; D057166:High-Throughput Screening Assays / Q000379:methods*; D008025:Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010802:Phylogeny; D010935:Plant Diseases / Q000382:microbiology; D011485:Protein Binding; D000072417:Protein Domains; D017386:Sequence Homology, Amino Acid; D012717:Sesquiterpenes / Q000378:metabolism*
D016573:Agrochemicals; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D012717:Sesquiterpenes; C013900:culmorin; C412581:longiborneol; D008025:Ligases
Culmorin; Ensemble docking; Fusarium mycotoxins; Homology modeling; Inhibitors; Molecular dynamics