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

第一作者： Yuan, Pengtao

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

作者机构：

关键词： Chitinase; inhibitor; conformation restriction; inhibitory mechanism

期刊名称：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 1475-6366

年卷期： 2025 年 40 卷 1 期

页码：

收录情况： SCI

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 & Aring;. 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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