Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase—a potential target to reduce Fusarium head blight disease

Abstract

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.

Chemical synthesis of culmorin metabolites and their biologic role in culmorin and acetyl-culmorin treated wheat cells

“…17 Although the evidence for a synergistic effect is still very limited, an enzyme involved in the biosynthesis of CUL has been proposed to be a target for mycotoxin reduction. 19 The role of CUL in plant-pathogen interaction is unknown.…”

Searching for Novel Targets to Control Wheat Head Blight Disease—I-Protein Identification, 3D Modeling and Virtual Screening

“…Once the target protein was identified as the most suitable template for homology modeling, we used MUSCLE 3.8.31 for multiple sequence alignment with default parameters to check for sequence similarity and to verify the conservation of structural signatures (find diagonals option disabled, a maximum number of iterations: 16, no duration limitation and no more than 200 sequences). The software MODELLER was used to perform the homology modeling task with its default settings [48]. The crude model for each selected target was obtained and equilibrated.…”