@article {16716,
	title = {Combined in silico and in vitro studies to identify novel antidiabetic flavonoids targeting glycogen phosphorylase},
	volume = {108},
	year = {2021},
	note = {n/a},
	month = {2021},
	pages = {104552},
	abstract = {<p>Novel pharmacological strategies for the treatment of diabetic patients are now focusing on inhibiting glycogenolysis steps. In this regard, glycogen phosphorylase (GP) is a validated target for the discovery of innovative antihyperglycemic molecules. Natural products, and in particular flavonoids, have been reported as potent inhibitors of GP at the cellular level. Herein, free-energy calculations and microscale thermophoresis approaches were performed to get an in-depth assessment of the binding affinities and elucidate intermolecular interactions of several flavonoids at the inhibitor site of GP. To our knowledge, this is the first study indicating genistein, 8-prenylgenistein, apigenin, 8-prenylapigenin, 8-prenylnaringenin, galangin and valoneic acid dilactone as natural molecules with high inhibitory potency toward GP. We identified: i) the residues Phe285, Tyr613, Glu382 and/or Arg770 as the most relevant for the binding of the best flavonoids to the inhibitor site of GP, and ii) the 5-OH, 7-OH, 8-prenyl substitutions in ring A and the 4'-OH insertion in ring B to favor flavonoid binding at this site. Our results are invaluable to plan further structural modifications through organic synthesis approaches and develop more effective pharmaceuticals for Type 2 Diabetes treatment, and serve as the starting point for the exploration of food products for therapeutic usage, as well as for the development of novel bio-functional food and dietary supplements/herbal medicines.</p>
},
	keywords = {Biophysical chemistry, Enzyme inhibition, Free-energy calculations, Microscale thermophoresis, Prenylflavonoids, Type 2 diabetes},
	isbn = {0045-2068},
	url = {https://www.sciencedirect.com/science/article/pii/S0045206820318502},
	author = {Br{\'a}s, Nat{\'e}rcia F. and Neves, Rui P.P. and Lopes, Filipa A.A. and Correia, M{\'a}rcia A. S. and Palma, Angelina S. and Sousa, S{\'e}rgio F. and Ramos, Maria J.}
}
