Virtual Screening of Hydrophobic Heterocyclic Compounds as Potential Insect Chitinase Inhibitors

Insect chitinases represent promising targets for the development of selective biorational insecticides. These enzymes degrade chitin during periodic molting, making them essential for insect survival. Consequently, disrupting their activity through targeted inhibition disrupts development and leads to lethality. In this study, a virtual screening of hydrophobic, nitrogen-containing heterocycles was performed against 31 PDB chitinase structures of the insect pest Ostrinia furnacalis using AutoDock Vina (5×5×5 nm grid box, chain A) to identify potential inhibitors.

Three polycyclic aromatic ligands demonstrated high binding affinities (expressed in kcal/mol) due to their planar structures and lipophilic nature. 1-(10H-phenoxazin-10-yl)hexan-1-one bound with energies from -9.4 to -9.0 to structures (5wvh, 5gpr, 7vrg, 5y2b, 6jaw, 3wl1, 5wvg, 6jmn, 6jay), while its sulfur analog, 1-(10H-phenothiazin-10-yl)hexan-1-one, exhibited affinity from -9.3 to -8.5 toward targets (6jaw, 5wvg, 6jav, 3wkz, 5y29, 3wl1, 6jay, 5y2b, 5y2c, 5wvb). The highest affinity interaction (-11.4 to -9.7) was obtained for 1,4-bis(5-phenyloxazol-2-yl)benzene (POPOP) with structures (6jaw, 6jav, 6jay, 5y29, 5y2b, 3wqv, 5wvg, 3wqw, 6jax, 3wl1, 5wvh, 5wv8).

These rigid aromatic systems effectively target the hydrophobic regions of the enzymes, driving stabilization via π-π stacking with tryptophan/tyrosine residues. For POPOP, the presence of multiple conjugated aromatic rings significantly enhances hydrophobic interactions within the active sites. Consequently, these frameworks represent interesting candidates for subsequent in vitro enzymatic validation.

Supported by BRFFR No. 20261794 and SPSR 'Chemical Processes and Technologies'.