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Mol Pharm. 2018 Mar 5;15(3):923-933. doi: 10.1021/acs.molpharmaceut.7b00871. Epub 2018 Feb 15.

Molecular Docking-Based Design and Development of a Highly Selective Probe Substrate for UDP-glucuronosyltransferase 1A10.

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School of Pharmacy, Faculty of Health Sciences , University of Eastern Finland , Box 1627, FI-70211 Kuopio , Finland.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy , University of Helsinki , P.O. Box 56, FI-00014 Helsinki , Finland.
Institute of Biomedicine, Faculty of Medicine , University of Turku , FI-20014 Turku , Finland.


Intestinal and hepatic glucuronidation by the UDP-glucuronosyltransferases (UGTs) greatly affect the bioavailability of phenolic compounds. UGT1A10 catalyzes glucuronidation reactions in the intestine, but not in the liver. Here, our aim was to develop selective, fluorescent substrates to easily elucidate UGT1A10 function. To this end, homology models were constructed and used to design new substrates, and subsequently, six novel C3-substituted (4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 4-methylphenyl, or triazole) 7-hydroxycoumarin derivatives were synthesized from inexpensive starting materials. All tested compounds could be glucuronidated to nonfluorescent glucuronides by UGT1A10, four of them highly selectively by this enzyme. A new UGT1A10 mutant, 1A10-H210M, was prepared on the basis of the newly constructed model. Glucuronidation kinetics of the new compounds, in both wild-type and mutant UGT1A10 enzymes, revealed variable effects of the mutation. All six new C3-substituted 7-hydroxycoumarins were glucuronidated faster by human intestine than by liver microsomes, supporting the results obtained with recombinant UGTs. The most selective 4-(dimethylamino)phenyl and triazole C3-substituted 7-hydroxycoumarins could be very useful substrates in studying the function and expression of the human UGT1A10.


7-hydroxycoumarin derivative; UDP-glucuronosyltransferase; drug metabolism; fluorescence; in silico

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