The study of inhibitory effect of natural flavonoids toward β-glucuronidase and interaction of flavonoids with β-glucuronidase
The study of inhibitory effect of natural flavonoids toward β-glucuronidase and interaction of flavonoids with β-glucuronidase
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DOI：
10.1016/j.ijbiomac.2019.12.057
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发表时间：
2020-01-15
影响因子：
8.2
通讯作者：
Ma, Xiaochi
中科院分区：
文献类型：
--
作者：
Sun, Cheng-Peng;Yan, Jian-Kun;Ma, Xiaochi
β-葡萄糖醛酸苷酶在药物和内源性物质的代谢中起着至关重要的作用。在此，我们用DDAO-Glu水解酶的探针反应检测了36个黄酮类化合物(1-36)对β-葡萄糖醛酸苷酶(EscherichiaColi)的抑制作用。结果表明，苦参素X(6)、(2S)-法瑞罗(10)、5，7，2‘-三羟基-8，6’-二甲氧基黄酮(20)、去甲基灯盏花素(31)和龙胆素(32)对β-葡萄糖醛酸苷酶有较强的抑制作用，IC50值分别为2.07+/-0.26、8.95+/-0.74、4.97+/-0.61、0.91+/-0.11和0.68+/-0.10mU/M。动力学研究表明，去甲基灯盏花素(31)和龙胆素(32)对β-葡萄糖醛酸酶呈混合型抑制作用，其KI值分别为4.05和2.02µM。此外，二向色性光谱的圆周变化证实了去甲基灯盏花素(31)和龙胆素(32)与β-葡萄糖苷酸酶的相互作用；随后的分子对接和分子动力学进一步揭示了β-葡萄糖醛酸酶中潜在的相互作用氨基酸位置。我们的发现不仅开发了一些有效的新型β-葡萄糖醛酸酶抑制剂，而且揭示了黄酮类化合物与一些具有肠-肝循环的临床药物潜在的药物相互作用(HDI)效应，进一步揭示了天然黄酮类化合物对β-葡萄糖苷酸酶抑制活性的重要药理需求。(C)2019爱思唯尔B.V.保留所有权利。
beta-Glucuronidase plays a vital role in the metabolism of drugs and endogenous substance. Herein, we assayed the inhibitory effects of thirty-six flavonoids (1-36) toward beta-glucuronidase (Escherichia coli) using the probe reaction of DDAO-glu hydrolysis. The results showed that kushenol X (6), (2S)-farrerol (10), 5,7,2'-trihydroxy-8,6'-dimethoxy flavone (20), demethylbellidifolin (31), and gentisin (32) exhibited potent inhibitory activities toward beta-glucuronidase with the IC50 values of 2.07 +/- 0.26, 8.95 +/- 0.74, 4.97 +/- 0.61, 0.91 +/- 0.11, and 0.68 +/- 0.10 mu M, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward beta-glucuronidase, the Ki values were caculated to be 4.05 and 2.02 mu M, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with beta-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in beta-glucuronidase. All our findings not only developed some potent novel beta-glucuronidase inhibitors but also indicated the potential herb drug interaction (HDI) effects of flavonoids with some clinical drugs which had enterohepatic circulation and further revealed the vital pharamcophoric requirement of natural flavonoids for beta-glucuronidase inhibition activity. (C) 2019 Elsevier B.V. All rights reserved.