Structure-guided computational insecticide discovery targeting -N-acetyl-D-hexosaminidase of Ostrinia furnacalis

Ostrinia furnacalis is a species of moth in the Crambidae family that is harmful to maize and other corn crops in Southeast Asia and the Western Pacific regions. Ostrinia furnacalis causes devastating losses to economically important corn fields. The beta-N-acetyl-D-hexosaminidase is an essential enzyme in O. furnacalis and its substrate binding +1 active site is different from that of the plants and humans beta-N-acetyl-D-hexosaminidases. To develop environment-friendly insecticides against OfHex1, we conducted structure-guided computational insecticide discovery to identify potential inhibitors that can bind the active site and inhibit the substrate binding and activity of the enzyme. We adopted a three-pronged strategy to conduct virtual screening using Glide and virtual screening workflow (VSW) in Schrodinger Suite-2022-3, against crystal structures of OfHex1 (PDB Id:3NSN), its homologue in humans (PDB Id: 1NP0) and Alphafold model of beta-N-acetyl-D-hexosaminidase from Trichogramma pretiosum, an egg parasitoid that protects the crops from O. furnacalis. A library of 20,313 commercially available and "insecticide-like" compounds was extracted from published literature. LigPrep enabled 44,943 ready-to-dock conformers generation. Glide docking revealed 18 OfHex1-specific hits that were absent in human and T. pretiosum screens. Reference docking was conducted using inhibitors/natural ligands in the crystal structures and hits with better docking scores than the reference were selected for MD simulations using Desmond to understand the stability of hit-target interactions. We noted five compounds that bound to OfHex1 TMX active-site based on their docking scores, consistent binding as noted by MD simulations and their insecticide/pesticide likeliness as noted by the Comprehensive Pesticide Likeness Analysis.