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NEW INSIGHTS INTO THE INHIBITION OF  beta-GLUCURONIDASE 

 

Shukufa JABBAROVA, Romy MASSFELLER, Khayala MAMMADOVA 

Baku State University, Medical University 

[e-mail],  [e-mail] 

 

β-Glucuronidase (β-D-glucuronide glucuronosohydrolase, (EC 3.2.1.31), belongs to the family of enzymes catalyzing 

the hydrolyses of glycosaminoglycans. The enzyme occurs in animal cells and their body fluids as well as in bacterial 

cells.Inhibition of β-glucuronidase   has attracted considerable attention due to a number of diseases and disorders 

associated with its elevated activity. Consequences of elevated levels of β–glucuronidase are numerous and have been 

observed at urinary diseases, epilepsy, and rheumatoid arthritis, in some hepatic diseases, AIDS, and different neoplastic 

conditions. Additionally, inhibition of symbiotic bacterial (E.coli) β-glucuronidase may alleviate cancer drug toxicity in 

colon cancer therapy since the bacterial glucuronidase in the gut is responsible for the side effects of commonly used colon 

cancer chemotherapeutics. Therefore, it is believed that the development of specific human and / or bacterial β  –

glucuronidase inhibitors is of great importance for pharmacology. Obviously, the identification of new inhibitors of β-

glucuronidase and in silico design of new potent inhibitors need more insights for the mechanisms of β-glucuronidase 

inhibition. 

In this work 58 individual compounds, acylhydrazide Schiff bases (class I, 12 compounds), unsymmetrically 

disubstituted ureas (class II, 10 compounds), aromatic sulfonyl hydrazides (class III, 28 compounds), and aromatic sulfones 

(8 compounds) have been synthesized and screened for β-glucuronidase in vitro inhibition. 31 out of 58 compounds of I-III 

showed inhibitory effect with IC

50

 values in the range 2.3 - 155.8 μM. No effective inhibitors were found among aromatic 

sulfones screened.  

Molecular docking studies have been performed using Autodock-Vina software. The studies reveal two principal 

binding modes of the inhibitors. Binding mode 1, characteristic for most inhibitors, occurs within the enzyme substrate 

pocket and involves interactions with the enzyme amino acid residues Glu413, Glu504 and Tyr472. Dissimilarly, binding of 

N-(3-chlorophenyl)-N’-(8-quinolinyl) urea (inhibitor II-4) occurs in the area adjacent, but beyond the canonical active 

center of β-glucuronidase (binding mode 2).  Binding mode 2 involves interactions with the residues His162, Val446, 

Met447, Ser557 and other different from the residues forming the substrate binding pocket.Unusual binding of compound 

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