title: Structure-activity relationships of flavonoids as natural inhibitors against E. coli β-glucuronidase.
abstract: Bacterial β-glucuronidases play key roles in the deconjugation of a variety of endogenous and drug glucuronides, thus have been recognized as important targets to modulate the enterohepatic circulation of various glucuronides. In this study, more than 30 natural flavonoids were collected and their inhibitory effects against E. coli β-glucuronidase (EcGUS) were assayed. The results demonstrated that some flavonoids including scutellarein, luteolin, baicalein, quercetin and scutellarin displayed strong to moderate inhibitory effects against EcGUS, with the IC50values ranging from 5.76 μM to 29.64 μM, while isoflavones and dihydroflavones displayed weak inhibitory effects against EcGUS. Further investigation on inhibition kinetics revealed that scutellarein and luteolin functioned as potent competitive inhibitors against EcGUS-mediated PNPG hydrolysis, with the Kivalues less than 3.0 μM. Molecular docking simulations demonstrated that scutellarein and luteolin could be well-docked into the catalytic site of EcGUS, while the binding areas of these two natural inhibitors on EcGUS were highly overlapped with that of PNPG on EcGUS. Additionally, the structure-inhibition relationships of natural flavonoids against EcGUS are also summarized, which will be very helpful for the medicinal chemists to design and develop more potent flavonoid-type inhibitors against EcGUS.
authors.affiliation: Dalian Medical University, Dalian 116044, China.
authors.forename: Zi-Miao
authors.initials: ZM
authors.lastname: Weng
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Zi-Ru
authors.initials: ZR
authors.lastname: Dai
authors.affiliation: Dalian Medical University, Dalian 116044, China.
authors.forename: Da-Chang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Zou
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Tong-Yi
authors.initials: TY
authors.lastname: Dou
authors.affiliation: Zhengzhou University of Light Industry, Zhengzhou 450001, China. Electronic address: zhangty@zzuli.edu.cn.
authors.forename: Tong-Yan
authors.initials: TY
authors.lastname: Zhang
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Dalian Medical University, Dalian 116044, China. Electronic address: houjie@dlmedu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D005419:Flavonoids; D005966:Glucuronidase
keywords: E. coli β-glucuronidases; Flavonoids; Luteolin; Scutellarein; Structure-inhibition relationships