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  3. 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

  • Int J Biol Macromol. 2020 Jan 15;143:349-358. doi: 10.1016/j.ijbiomac.2019.12.057.
Cheng-Peng Sun 1,  Jian-Kun Yan 2,  Jing Yi 1,  Xin-Yue Zhang 1,  Zhen-Long Yu 1,  Xiao-Kui Huo 1,  Jia-Hao Liang 1,  Jing Ning 1,  Lei Feng 1,  Chao Wang 1,  Bao-Jing Zhang 1,  Xiang-Ge Tian 3,  Lin Zhang 4,  Xiaochi Ma 5
Affiliations

Affiliations

  • 1 College of Pharmacy, College of Integrative Medicine, The National & Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease, Dalian Medical University, Dalian, China.
  • 2 Analysis Center of College of Science & Technology, Hebei Agricultural University, Cangzhou, Hebei, China.
  • 3 College of Pharmacy, College of Integrative Medicine, The National & Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease, Dalian Medical University, Dalian, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China. Electronic address: [email protected].
  • 4 College of Pharmacy, College of Integrative Medicine, The National & Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease, Dalian Medical University, Dalian, China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
PMID: 31830453 DOI: 10.1016/j.ijbiomac.2019.12.057
Abstract

β-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 β-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 β-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 μM, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward β-glucuronidase, the Ki values were caculated to be 4.05 and 2.02 μM, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with β-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in β-glucuronidase. All our findings not only developed some potent novel β-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 β-glucuronidase inhibition activity.

Keywords

Drug and drug interaction; Flavonoid; Molecular interaction; β-Glucuronidase.

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