Discovery of potent α-glucosidase inhibitor flavonols: Insights into mechanism of action through inhibition kinetics and docking simulations

• Published in: Bioorganic chemistry Vol. 79; pp. 257 - 264
• Main Authors: Şöhretoğlu, Didem, Sari, Suat, Barut, Burak, Özel, Arzu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2018
• Subjects: alpha-Glucosidases - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Enzyme kinetics; Flavonoid; Flavonol; Flavonols - chemical synthesis; Flavonols - chemistry; Flavonols - pharmacology; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Humans; Kinetics; Molecular docking; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; α-glucosidase; α-glucosidase; ALBS; DM; Flavonol; OLBS; Enzyme kinetics; SCM; Flavonoid; Molecular docking
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.05.010

[Display omitted] •A set of flavonols were tested for their α-glucosidase inhibition.•Glycosylation of the C-3 hydroxyl decreased the activity.•Galloyl substitution to sugar unit increased the α-glucosidase inhibitory effect.•Molecular docking of 1, 2, 7–9 predicted good fit and high affinity to the enzyme. Beside other pharmaceutical benefits, flavonoids are known for their potent α-glucosidase inhibition. In the present study, we investigated α-glucosidase inhibitory effects of structurally related 11 flavonols, among which quercetin-3-O-(3″-O-galloyl)-β-galactopyranoside (8) and quercetin 3-O-(6″-O-galloyl)-β-glucopyranoside (9) showed significant inhibition compared to the positive control, acarbose, with IC50 values of 0.97 ± 0.02 and 1.35 ± 0.06 µM, respectively. It was found that while sugar substitution to C3-OH of C ring reduced the α-glucosidase inhibitory effect, galloyl substitution to these sugar units increased it. An enzyme kinetics analysis revealed that 7 was competitive, whereas 1, 2, 8, and 9 were uncompetitive inhibitors. In the light of these findings, we performed molecular docking studies to predict their inhibition mechanisms at atomic level.