Glycosyl triazoles as novel insect β-N-acetylhexosaminidase OfHex1 inhibitors: Design, synthesis, molecular docking and MD simulations

Abstract

The insect enzyme GH20 β-N-acetyl-d-hexosaminidase OfHex1 represents an important chitinolytic enzyme found in the agricultural pest Ostrinia furnacalis (Guenée) and inhibition of this enzyme has been considered a promising strategy for the development of eco-friendly pesticides. In this article, based on the structure of the catalytic domains of OfHex1, a series of novel glycosyl triazoles were designed and synthesized via Cu-catalyzed azide-alkyne [3+2] cycloaddition reaction. To investigate the potency and selectivity of these glycosyl triazoles, the inhibition activities towards OfHex1 and HsHexB (human β-N-acetylhexosaminidase B) were studied. Particularly compound 17c (OfHex1, K_i = 28.68 μM; HsHexB, K_i > 100 μM) exhibited a suitable activity and selectivity against OfHex1. Furthermore, the possible inhibitory mechanisms of 17c with OfHex1 were studied using molecular docking and MD simulations. The structure-activity relationship results as well as the formed binding patterns may provide promising insights into the further development of novel OfHex1 inhibitors.

Keywords: Enzyme inhibitors; Glycosyl triazoles; MD simulations; Molecular docking; OfHex1; β-N-acetyl-d-hexosaminidase.