α-Glucosidase inhibitory effects of polyphenols from Geranium asphodeloides: Inhibition kinetics and mechanistic insights through in vitro and in silico studies

• Published in: Bioorganic chemistry 2018-12, Vol.81, p.545-552
• Main Authors: Renda, Gülin, Sari, Suat, Barut, Burak, Šoral, Michal, Liptaj, Tibor, Korkmaz, Büşra, Özel, Arzu, Erik, İshak, Şöhretoğlu, Didem
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases - metabolism; Flavonoid; Geraniaceae; Geranium - chemistry; Geranium asphodeloides; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Molecular Docking Simulation; Plant Extracts - chemistry; Plant Extracts - pharmacology; Polyphenols - chemistry; Polyphenols - pharmacology; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae Proteins - metabolism; Tannin; α-Glucosidase
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.09.009

[Display omitted] •Extracts and compounds from G. asphodeloides proved potent α-glucosidase inhibitors.•1 showed the strongest α-glucosidase inhibitory effect among the isolated compounds.•1 was approximately 61 fold more effective than positive control, acarbose.•2, 3 and 4 were competitive; 1 and 6 were uncompetitive inhibitors.•Molecular docking studies gave insights into inhibition mechanisms of the compounds. Some Geranium species have been used to treat diabetes. To evaluate the scientific basis of this ethnopharmacological use, we aimed to isolate potent α-glucosidase inhibitory metabolites of Geranium asphodeloides Burm. through in vitro bioactivity-guided fractionation. All the tested extracts showed high α-glucosidase inhibitory effect compared to acarbose. Among the tested extracts, the ethyl acetate subextract showed the highest activity with an IC50 value of 0.85 ± 0.01 µM. A hydrolysable tannin, 1,2,4-tri-O-galloyl-β-d-glucopyranose (1), and five flavonoid glycosides, kaempferol-3-O-α-rhamnopyranoside (2), kaempferol-3-O-α-arabinofuranoside (3), quercetin-3-O-β-glucopyranoside (4), quercetin-3-O-α-rhamnopyranoside (5), and quercetin-3-O-α-rhamnofuranoside (6), were isolated from the ethyl acetate subextract. Their structures were identified by 1D- and 2D-NMR experiments. 1 exhibited the highest α-glucosidase inhibitory effect, approximately 61 times more potent than positive control, acarbose, with an IC50 value of 0.95 ± 0.07 µM. Also, 2 was more potent than acarbose. An enzyme kinetics analysis revealed that compounds 2, 3 and 4 were competitive, whereas 1 and 6 uncompetitive inhibitors. Molecular docking studies were performed to get insights into inhibition mechanisms of the isolated compounds in the light of the enzyme kinetic studies using various binding sites of the enzyme model.