Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 M) shows a higher inhibiting ability than compound 7145 (IC50=31.6 M) 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.

Original languageEnglish
Article number740815
JournalScientific World Journal
Volume2015
DOIs
Publication statusPublished - 2015

Fingerprint

Glucuronidase
carcinogen
Computer Simulation
Escherichia coli
inhibitor
Screening
molecular analysis
detoxification
metabolism
hydrogen
Carcinogenesis
Carcinogens
Inhibitory Concentration 50
Reactive Oxygen Species
Molecular Docking Simulation
reactive oxygen species
screening
1,2-Dimethylhydrazine
Butanones
Detoxification

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Environmental Science(all)
  • Medicine(all)

Cite this

Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening. / Cheng, Ta Chun; Chuang, Kuo Hsiang; Roffler, Steve R.; Cheng, Kai Wen; Leu, Yu Lin; Chuang, Chih Hung; Huang, Chien Chaio; Kao, Chien Han; Hsieh, Yuan Chin; Chang, Long Sen; Cheng, Tian Lu; Chen, Chien Shu.

In: Scientific World Journal, Vol. 2015, 740815, 2015.

Research output: Contribution to journalArticle

Cheng, TC, Chuang, KH, Roffler, SR, Cheng, KW, Leu, YL, Chuang, CH, Huang, CC, Kao, CH, Hsieh, YC, Chang, LS, Cheng, TL & Chen, CS 2015, 'Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening', Scientific World Journal, vol. 2015, 740815. https://doi.org/10.1155/2015/740815
Cheng, Ta Chun ; Chuang, Kuo Hsiang ; Roffler, Steve R. ; Cheng, Kai Wen ; Leu, Yu Lin ; Chuang, Chih Hung ; Huang, Chien Chaio ; Kao, Chien Han ; Hsieh, Yuan Chin ; Chang, Long Sen ; Cheng, Tian Lu ; Chen, Chien Shu. / Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening. In: Scientific World Journal. 2015 ; Vol. 2015.
@article{2929bf0833d34795b3077d03381fb636,
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 M) shows a higher inhibiting ability than compound 7145 (IC50=31.6 M) 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.",
author = "Cheng, {Ta Chun} and Chuang, {Kuo Hsiang} and Roffler, {Steve R.} and Cheng, {Kai Wen} and Leu, {Yu Lin} and Chuang, {Chih Hung} and Huang, {Chien Chaio} and Kao, {Chien Han} and Hsieh, {Yuan Chin} and Chang, {Long Sen} and Cheng, {Tian Lu} and Chen, {Chien Shu}",
year = "2015",
doi = "10.1155/2015/740815",
language = "English",
volume = "2015",
journal = "The Scientific World Journal",
issn = "2356-6140",
publisher = "Hindawi Publishing Corporation",

}

TY - JOUR

T1 - Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening

AU - Cheng, Ta Chun

AU - Chuang, Kuo Hsiang

AU - Roffler, Steve R.

AU - Cheng, Kai Wen

AU - Leu, Yu Lin

AU - Chuang, Chih Hung

AU - Huang, Chien Chaio

AU - Kao, Chien Han

AU - Hsieh, Yuan Chin

AU - Chang, Long Sen

AU - Cheng, Tian Lu

AU - Chen, Chien Shu

PY - 2015

Y1 - 2015

N2 - 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 M) shows a higher inhibiting ability than compound 7145 (IC50=31.6 M) 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.

AB - 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 M) shows a higher inhibiting ability than compound 7145 (IC50=31.6 M) 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.

UR - http://www.scopus.com/inward/record.url?scp=84925763792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925763792&partnerID=8YFLogxK

U2 - 10.1155/2015/740815

DO - 10.1155/2015/740815

M3 - Article

C2 - 25839056

AN - SCOPUS:84925763792

VL - 2015

JO - The Scientific World Journal

JF - The Scientific World Journal

SN - 2356-6140

M1 - 740815

ER -