Natural constituents from Cortex Mori Radicis as new pancreatic lipase inhibitors
Natural constituents from Cortex Mori Radicis as new pancreatic lipase inhibitors
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桑皮的天然成分作为新型胰腺脂肪酶抑制剂
DOI：
10.1016/j.bioorg.2018.07.011
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发表时间：
2018-10-01
影响因子：
5.1
通讯作者：
Hou, Jie
中科院分区：
文献类型：
--
作者：
Hou, Xu-Dong;Ge, Guang-Bo;Hou, Jie
胰脂肪酶（PL）是胃肠道中负责水解三酰甘油的关键酶，已被确定为调节脂质吸收的治疗靶点。在本研究中，收集了著名中草药桑白皮（中文也称为桑白皮）中的六种主要成分，并通过基于荧光的测定仔细研究并充分表征了它们对 PL 的抑制作用。结果清楚地表明桑根酮 C (SC)、桑根酮 D (SD)、桑根酮 C (KC)、桑根酮 G (KG)、桑色素和桑色素对 PL 具有强至中度的抑制作用，IC50 值范围为 0.77 μM 至 20.56 μM。抑制作用的进一步研究 动力学表明，SC、SD、KC 和 KG 作为 PL 介导的 4-MU 油酸水解的有效混合抑制剂，K-i 值小于 5.0 μM。此外，分子对接模拟表明，SD（桑皮中最有效的 PL 抑制剂）可以与 Ser152（催化三联体中的关键氨基酸）产生强相互作用。 PL 通过氢键作用。这些发现为解释桑皮的降血脂作用提供了新的有力证据，也表明桑皮中一些丰富的天然化合物可以作为开发新型PL抑制剂的先导化合物。
Pancreatic lipase (PL), a key enzyme responsible for the hydrolysis of triacylglycerides in the gastrointestinal tract, has been identified as the therapeutic target for the regulation of lipid absorption. In the present study, six major constituents from a famous Chinese herbal medicine Cortex Mori Radicis (also named sangbaipi in Chinese), have been collected and their inhibitory effects on PL have been carefully investigated and well characterized by a fluorescence-based assay. The results clearly demonstrated that all tested bioactive constituents from Cortex Mori Radicis including sanggenone C (SC), sanggenone D (SD), kuwanon C (KC), kuwanon G (KG), morin and morusin displayed strong to moderate inhibitory effects towards PL with the IC50 values ranging from 0.77 mu M to 20.56 mu M. Further investigations on inhibition kinetics demonstrated that SC, SD, KC and KG functioned as potent and mixed inhibitors against PL-mediated 4-MU oleate hydrolysis, with the K-i values less than 5.0 mu M. Furthermore, molecular docking simulations demonstrated that SD (the most potent PL inhibitor from Cortex Mori Radicis) could create strong interaction with Ser152 (the key amino acid in the catalytic triad) of PL via hydrogen bonding. All these findings provided a new powerful evidence for explaining the hypolipidemic effect of Cortex Mori Radicis, also suggested that some abundant natural compounds in this herbal medicine could be served as lead compounds for the development of new PL inhibitors.