数字农科院2.0

Discovery of conformation constrained tetracyclic compounds as potent chitinase OfChi-h inhibitors with a novel binding mode

文献类型： 外文期刊

作者： Pengtao Yuan;Xi Jiang;Xintong Ni;Xusheng Shao;Xuhong Qian;Qing Yang

关键词： Chitinase conformation restriction inhibitor inhibitory mechanism Animals Binding Sites Chitinases Dose-Response Relationship; Drug Drug Discovery Enzyme Inhibitors Molecular Conformation Molecular Docking Simulation Molecular Structure Moths Structure-Activity Relationship chitinase inhibitor dipyridopyrimidine 3 carboxamide derivative glycosidase inhibitor hydrogen unclassified drug enzyme inhibitor agricultural pest Article carbon nuclear magnetic resonance catalysis column chromatography conformation crystallization drug protein binding enzyme inhibition hydrogen bond mass spectrometry molecular docking nonhuman nuclear magnetic resonance spectroscopy Ostrinia furnacalis pest control proton nuclear magnetic resonance Serratia marcescens structure activity relation animal binding site chemical structure chemistry dose response drug development drug effect enzymology metabolism moth synthesis

期刊名称： JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

ISSN： 1475-6366

年卷期： 2025 年

页码：

收录情况： SCIE（2025版）

摘要： Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage OfChi-h from destructive agricultural pest Ostrinia furnacalis (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel OfChi-h inhibitors. Among these, compound 6a showed the highest inhibitory activity against OfChi-h, with a Ki value of 58 nM. Molecular docking analysis suggested that 6a tightly bound to three subsites (-3 to −1) of OfChi-h. The binding mode is further confirmed by the co-crystallization data of 6a with the SmChiA, a bacterial homologue of OfChi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.

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