Natural flavonoid α-glucosidase inhibitors from Retama raetam: Enzyme inhibition and molecular docking reveal important interactions with the enzyme active site.

Retama raetam (Forsk.) Webb & Berthel plant has been traditionally used for the treatment of diabetes mellitus and hypertension. Interest in the medicinal chemistry of the plant in the past resulted in the isolation of a number of compounds with anti-hyperglycemic activity. The current work is a further extension of our recent work in which we isolated and characterized seven new flavonoids from Retama raetam with preliminary biological activity screening. It addresses the α-glucosidase inhibitory activity and molecular docking studies of the flavonoids. Retamasin D, G, H, and erysubin A and B noncompetitively inhibited the enzyme whereas retamasin C and F exhibited competitive inhibition. Moreover, retamasin C, F, G, and erysubin A and B carry dual activity in addition to α-glucosidase inhibition. Our previous studies have shown that they also caused significant stimulation of insulin from the blood-perfused pancreatic islets of Langerhans of mice. The C6 and C8 substituent groups greatly influenced the inhibition potency of the compounds. The most potent inhibitor was retamasin H with the γ-lactone ring substituent at C6 position of the main flavonoid moiety. Notable active chemical groups in the target compounds include γ-lactone, dihydropyran and dihydrofuran rings with hydroxyl and geminal methyl groups. Molecular modeling studies revealed that the compounds fit well in the α-glucosidase active site by interacting with important active site residues. These findings will incorporate new chemical, structural and functional diversity to the search and drug development of α-glucosidase inhibitors as anti-diabetic drugs.