Structure-guided computational insecticide discovery targeting <i>β</i>-N-acetyl-D-hexosaminidase of <i>Ostrinia furnacalis</i>

<i>Ostrinia furnacalis</i> 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. <i>Ostrinia furnacalis</i> causes devastating losses to economically important corn fields. The β-N-acetyl-D-hexosaminidase is an essential enzyme in <i>O. furnacalis</i> and its substrate binding +1 active site is different from that of the plants and humans β-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 Schrödinger Suite-2022-3, against crystal structures of OfHex1 (PDB Id:3NSN), its homologue in humans (PDB Id: 1NP0) and Alphafold model of β-N-acetyl-D-hexosaminidase from <i>Trichogramma pretiosum</i>, an egg parasitoid that protects the crops from <i>O. furnacalis.</i> 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 <i>T. pretiosum</i> 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. Communicated by Ramaswamy H. Sarma