Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening
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 carcin...
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| Language: | English |
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Wiley
2015-01-01
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| Series: | The Scientific World Journal |
| Online Access: | http://dx.doi.org/10.1155/2015/740815 |
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| author | Ta-Chun Cheng Kuo-Hsiang Chuang Steve R. Roffler Kai-Wen Cheng Yu-Lin Leu Chih-Hung Chuang Chien-Chaio Huang Chien-Han Kao Yuan-Chin Hsieh Long-Sen Chang Tian-Lu Cheng Chien-Shu Chen |
| author_facet | Ta-Chun Cheng Kuo-Hsiang Chuang Steve R. Roffler Kai-Wen Cheng Yu-Lin Leu Chih-Hung Chuang Chien-Chaio Huang Chien-Han Kao Yuan-Chin Hsieh Long-Sen Chang Tian-Lu Cheng Chien-Shu Chen |
| author_sort | Ta-Chun Cheng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0a2b3e96bd444eb69a82c2dac885205c |
| institution | Kabale University |
| issn | 2356-6140 1537-744X |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | The Scientific World Journal |
| spelling | doaj-art-0a2b3e96bd444eb69a82c2dac885205c2025-08-20T03:55:27ZengWileyThe Scientific World Journal2356-61401537-744X2015-01-01201510.1155/2015/740815740815Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual ScreeningTa-Chun Cheng0Kuo-Hsiang Chuang1Steve R. Roffler2Kai-Wen Cheng3Yu-Lin Leu4Chih-Hung Chuang5Chien-Chaio Huang6Chien-Han Kao7Yuan-Chin Hsieh8Long-Sen Chang9Tian-Lu Cheng10Chien-Shu Chen11Graduate Institute of Pharmacognosy, Taipei Medical University, 252 Wu Hsing Street, Taipei 11031, TaiwanGraduate Institute of Pharmacognosy, Taipei Medical University, 252 Wu Hsing Street, Taipei 11031, TaiwanInstitute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Nankang, Taipei 11529, TaiwanInstitute of Biomedical Science, 70 Lienhai Road, Kaohsiung 80424, National Sun Yat-Sen University, TaiwanDepartment of Pharmacy, Chia Nan University of Pharmacy and Science, 60 Section 1, Erh-Ren Road, Tainan 71710, TaiwanDepartment of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanDepartment of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanGraduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanGraduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanInstitute of Biomedical Science, 70 Lienhai Road, Kaohsiung 80424, National Sun Yat-Sen University, TaiwanDepartment of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, TaiwanSchool of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, TaiwanGlucuronidation 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.http://dx.doi.org/10.1155/2015/740815 |
| spellingShingle | Ta-Chun Cheng Kuo-Hsiang Chuang Steve R. Roffler Kai-Wen Cheng Yu-Lin Leu Chih-Hung Chuang Chien-Chaio Huang Chien-Han Kao Yuan-Chin Hsieh Long-Sen Chang Tian-Lu Cheng Chien-Shu Chen Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening The Scientific World Journal |
| title | Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening |
| title_full | Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening |
| title_fullStr | Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening |
| title_full_unstemmed | Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening |
| title_short | Discovery of Specific Inhibitors for Intestinal E. coli β-Glucuronidase through In Silico Virtual Screening |
| title_sort | discovery of specific inhibitors for intestinal e coli β glucuronidase through in silico virtual screening |
| url | http://dx.doi.org/10.1155/2015/740815 |
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