Crystal structure-guided design of berberine-based novel chitinase inhibitors

文献类型： 外文期刊

第一作者： Chen, Lei

作者： Chen, Lei;Chen, Jinli;Yang, Qing;Chen, Lei;Chen, Wei;Yang, Qing;Zhu, Ling;Qian, Xuhong;Yang, Qing

作者机构：

关键词： Berberine; chitinase; inhibitor; structural optimisation

期刊名称：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY （ 影响因子：5.051； 五年影响因子：4.598 ）

ISSN： 1475-6366

年卷期： 2020 年 35 卷 1 期

页码：

收录情况： SCI

摘要： Glycoside hydrolase family 18 (GH18) chitinases play an important role in various organisms ranging from bacteria to mammals. Chitinase inhibitors have potential applications as pesticides, fungicides, and anti-asthmatics. Berberine, a plant-derived isoquinoline alkaloid, was previously reported to inhibit against various GH18 chitinases with only moderate K (i) values ranging between 20 and 70 mu M. In this report, we present for the first time the berberine-complexed crystal structure of SmChiB, a model GH18 chitinase from the bacterium Serratia marcescens. Based on the berberine-binding mode, a hydrophobic cavity-based optimisation strategy was developed to increase their inhibitory activity. A series of berberine derivatives were designed and synthesised, and their inhibitory activities against GH18 chitinases were evaluated. The compound 4c showed 80-fold-elevated inhibitory activity against SmChiB and the human chitinase hAMCase with K (i) values at the sub-micromolar level. The mechanism of improved inhibitory activities was proposed. This work provides a new strategy for developing novel chitinase inhibitors.

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