The study of inhibitory effect of natural flavonoids toward β-glucuronidase and interaction of flavonoids with β-glucuronidase

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.