Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2020-11-09 , DOI: 10.1080/14756366.2020.1837123 Lei Chen 1, 2 , Ling Zhu 3 , Jinli Chen 1 , Wei Chen 2 , Xuhong Qian 3 , Qing Yang 1, 2, 4
Abstract
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 μM. 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.
中文翻译:
基于小ber碱的新型几丁质酶抑制剂的晶体结构指导设计
摘要
糖苷水解酶家族18(GH18)几丁质酶在从细菌到哺乳动物的各种生物中起着重要作用。几丁质酶抑制剂作为农药,杀真菌剂和抗哮喘药具有潜在的应用。黄连素,植物来源的异喹啉生物碱,先前被报道对各种GH18几丁质酶抑制与仅具有中等ķ 我值范围μM20和70之间。在本报告中,我们首次展示了Sm ChiB的小ber碱复合晶体结构,Sm ChiB是一种来自粘质沙雷氏菌的模型GH18几丁质酶。。基于小ber碱结合模式,开发了基于疏水腔的优化策略以增加其抑制活性。设计并合成了一系列小碱衍生物,并评估了它们对GH18几丁质酶的抑制活性。化合物4c对Sm ChiB和人几丁质酶hAMCase的抑制活性提高了80倍,K i值在亚微摩尔水平。提出了抑制活性提高的机理。这项工作为开发新型几丁质酶抑制剂提供了新的策略。