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- Title
An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles.
- Authors
Rocha, Sónia; Aniceto, Natália; Guedes, Rita C.; Albuquerque, Hélio M. T.; Silva, Vera L. M.; Silva, Artur M. S.; Corvo, Maria Luísa; Fernandes, Eduarda; Freitas, Marisa
- Abstract
Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure–activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC50 < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors.
- Subjects
COMPUTER simulation; IN vitro studies; EXPERIMENTAL design; FLAVONOIDS; HETEROCYCLIC compounds; HYPOGLYCEMIC agents; BLOOD sugar; ORGANIC compounds; TYPE 2 diabetes; TRANSFERASES; HYPOGLYCEMIA; CHROMONES; MOLECULAR structure; COMPUTER-assisted molecular modeling; PHARMACODYNAMICS
- Publication
Nutrients, 2022, Vol 14, Issue 2, p306
- ISSN
2072-6643
- Publication type
Article
- DOI
10.3390/nu14020306