Identification of novel insect β-N-acetylhexosaminidase OfHex1 inhibitors based on virtual screening, biological evaluation, and molecular dynamics simulation.

Chitin can be widely found in the fungal cell wall, nematode eggshells, and the exoskeleton of arthropods; however, it is completely absent from higher plants and mammals. The process of chitin degradation is essential for both growth and maturation of insects. Thus, inhibiting chitin degradation is a promising strategy for the control and management of pests. The chitinolytic β-N-acetyl-D-hexosaminidase OfHex1 of Ostrinia furnacalis (one of the most destructive pests) has been suggested as a potential target for the design of eco-friendly pesticides. This study presents the sequential virtual screening of the ZINC library with 8 million compounds, targeting OfHex1. After confirmation via enzyme inhibition experiments, compound 5 exhibited potential inhibitory activity against OfHex1 with a Ki of 28.9 ± 0.5 μM and significant selectivity (IC50 > 100 μM against HsHexB and hOGA). Molecular dynamics simulations combined with binding free energy and free energy decomposition calculations were conducted to investigate the molecular basis underlying the potency of these inhibitors toward OfHex1. The present work provides useful information for the future rational design of novel and potent OfHex1 inhibitorsCommunicated by Ramaswamy H. Sarma.