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

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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

ASJC Scopus subject areas

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

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    Cheng, T. C., Chuang, K. H., Roffler, S. R., Cheng, K. W., Leu, Y. L., Chuang, C. H., Huang, C. C., Kao, C. H., Hsieh, Y. C., Chang, L. S., Cheng, T. L., & Chen, C. S. (2015). Discovery of specific inhibitors for intestinal E. coli β -glucuronidase through in silico virtual screening. Scientific World Journal, 2015, [740815]. https://doi.org/10.1155/2015/740815