X-ray Structure and Molecular Docking Guided Discovery of Novel Chitinase Inhibitors with a Scaffold of Dipyridopyrimidine-3-carboxamide

文献类型： 外文期刊

第一作者： Yuan, Pengtao

作者： Yuan, Pengtao;Shao, Xusheng;Qian, Xuhong;Jiang, Xi;Wang, Siyu;Yang, Qing;Shao, Xusheng;Qian, Xuhong;Qian, Xuhong

作者机构：

关键词： chitinase; inhibitor; X-ray structure; pest control

期刊名称：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY （ 影响因子：5.279； 五年影响因子：5.269 ）

ISSN： 0021-8561

年卷期： 2020 年 68 卷 47 期

页码：

收录情况： SCI

摘要： Chitinases are the glycosyl hydrolase for catalyzing the degradation of chitin and play an indispensable role in bacterial pathogenesis, fungal cell wall remodeling, and insect molting. Thus, chitinases are attractive targets for therapeutic drugs and pesticides. Here, we present a strategy of developing a novel chemotype of chitinase inhibitors by the construction of planar heterocycles that can stack with conserved aromatic residues. The rational design, guided by crystallographic analysis and docking results, leads to a series of dipyridopyrimidine-3-carboxamide derivatives as chitinase inhibitors. Among them, compound 6t showed the most potent activity against bacterial chitinase SmChiB and insect chitinase Of Chi-h, with a K-i value of 0.14 and 0.0056 mu M, respectively. The strong stacking interaction of compound 6p with Trp99 and Trp220 found in the SmChiB-6p co-crystal structure verifies the feasibility of our design. Our results provide novel insights into developing potent chitinase inhibitors for pathogen and pest control.

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