Combined in silico and in vitro studies to identify novel antidiabetic flavonoids targeting glycogen phosphorylase

• Tipo: Artigo em Revista Científica Internacional
• Data: 2021

Autores

Natercia F Bras (Autor) FCUP; Neves, RPP (Autor) FCUP; Lopes, FAA (Autor) Outra; Correia, MAS (Autor) Outra; Palma, AS (Autor) Outra; Sergio Filipe Sousa (Autor) FCUP; Ramos, MJ (Autor) FCUP

Revista

Título: Bioorganic Chemistry

Vol. 108

ISSN: 0045-2068

Editora: Elsevier

Indexação

ISI Web of Knowledge - 5 Citações

Scopus - 5 Citações

Outras Informações

ID Authenticus: P-00T-8VV

DOI: 10.1016/j.bioorg.2020.104552

Abstract (EN): 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 10