Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan
Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan
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DOI：
10.1016/j.jep.2016.03.063
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发表时间：
2016-06-20
影响因子：
5.4
通讯作者：
Koike, Kazuo
中科院分区：
文献类型：
--
作者：
Onoda, Toshihisa;Li, Wei;Koike, Kazuo
民族药理学相关性：Masiningan是一种由六种生药组成的传统药物，在日本和中国都被用于治疗便秘和糖尿病。据报道，Masiningan具有显著的PTP 1B抑制活性，并影响胰岛素信号通路中的细胞。本研究的目的是确定的PTP 1B抑制化合物Masiningan.Materials和方法：生物活性峰的分析HPLC分析和PTP 1B抑制活性分析的亚组分从Masiningan提取物。通过跟踪两个确定的生物活性峰来分离生物活性化合物，并通过光谱分析来确定化学结构。通过酶动力学分析、分子对接模拟、对其他PTP的抑制选择性以及胰岛素信号转导途径中的细胞活性进一步研究了生物活性化合物对PTP 1B的抑制作用。从Masiningan中分离出厚朴酚（1）和大黄酚（2），它们对PTP 1B表现出显著的剂量依赖性抑制活性，IC 50值分别为24.6和12.3 μ M。动力学分析表明，1是一个非竞争性和2是一个竞争性的PTP 1B抑制剂。在分子对接模拟中，化合物2被稳定地定位在PTP 1B的活性口袋中，并且计算出CDOCKER能量为24.3411 kcal/mol。结论：厚朴酚（1）和大黄酚（2）是马斯宁安中主要的PTP 1B抑制活性化合物，并对它们的作用进行了详细的研究。这些发现证明了Masiningan通过在分子水平上抑制PTP 1B对糖尿病的有效性，以及厚朴酚（1）和大黄酚（2）作为未来抗糖尿病药物开发中的先导化合物的潜力。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: Masiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan.Materials and methods: Bioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway.Results: From Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3 mu M, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411 kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway.Conclusions: Magnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development. (C) 2016 Elsevier Ireland Ltd. All rights reserved.