Discovery of specific inhibitors for intestinal E. coli???-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 ???-glucuronidase (e?G) has been considered pivotal to colorectal carcinogenesis. Specific inhibition of e?G may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific e?G inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against e?G but not human ?G. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS) are highly effective and selective to inhibit e?G activity. Compound 4041??(IC50 = 2.8??M) shows a higher inhibiting ability than compound 7145??(IC50 = 31.6??M) against e?G. 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 e?G via hydrogen-bonding interactions. These novel NYBS-based e?G specific inhibitors may provide as novel candidate compounds, which specifically inhibit e?G to reduce e?G-based carcinogenesis and intestinal injury.

SUBMITTER: Cheng TC 

PROVIDER: S-EPMC4370192 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature