title: Discovery of specific inhibitors for intestinal E. coli  β-glucuronidase through in silico virtual screening.
abstract: Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino)-1-(3-pyridy)-1-butanone (NNK) and 1,2-dimethylhydrazine (DMH), of reactive oxygen species (ROS). However, intestinal E. coli   β-glucuronidase (eβG) has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS) are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50 = 2.8 μM) shows a higher inhibiting ability than compound 7145  (IC50 = 31.6 μM) against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413) at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 252 Wu Hsing Street, Taipei 11031, Taiwan.
authors.forename: Ta-Chun
authors.initials: TC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 252 Wu Hsing Street, Taipei 11031, Taiwan.
authors.forename: Kuo-Hsiang
authors.identifier: 0000-0001-7513-2671
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Nankang, Taipei 11529, Taiwan.
authors.forename: Steve R
authors.identifier: 0000-0003-2543-7295
authors.initials: SR
authors.lastname: Roffler
authors.affiliation: Institute of Biomedical Science, National Sun Yat-Sen University, 70 Lienhai Road, Kaohsiung 80424, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy, Chia Nan University of Pharmacy and Science, 60 Section 1, Erh-Ren Road, Tainan 71710, Taiwan.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Leu
authors.affiliation: Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chuang
authors.affiliation: Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
authors.forename: Chien-Chaio
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
authors.forename: Chien-Han
authors.identifier: 0000-0002-3910-9391
authors.initials: CH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
authors.forename: Yuan-Chin
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Science, National Sun Yat-Sen University, 70 Lienhai Road, Kaohsiung 80424, Taiwan.
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
authors.affiliation: Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan ; Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan ; Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
authors.forename: Tian-Lu
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Chien-Shu
authors.identifier: 0000-0002-2041-3975
authors.initials: CS
authors.lastname: Chen
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000502:physiology; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D017433:Protein Structure, Secondary
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D005966:Glucuronidase
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