Abstract
The type A proanthocyanidins (2−8) with (2<i>β</i>→O→7, 4<i>β</i>→8) interflavane linkage, isolated from <i>Machilus philippinensis</i>, have been found to possess inhibitory activity against <i>α</i>-glucosidase (EC 3.2.1.20 from <i>Bacillus stearothermophilus</i>). To rationalize such activity, computer assisted docking of these compounds and the positive control, acarbose, on the conformation model of <i>α</i>-glucosidase (AG), built by using human intestinal maltase glucoamylase as a template, was undertaken in this study. The result showed good correlation between IC<sub>50</sub> values and docking scores, expressed as binding energy (ΔG), obtained from London (trimatch)-refinement (forcefield AffinityΔG) mode. Among these isolates, the most potent aesculitannin B (2) (IC<sub>50</sub> 3.5<i>μ</i>M) showed the best docking score (ΔG -21.48 kcal/mol). Being interested in clarification of structure and activity relationship, virtual screening on the related compounds, including the de-unit III homologs of 2−8 (<i>i.e.</i>, nor- series) and additional 13 stereoisomers of the trimeric 2 at the C-2 and C-3 positions of units II and III, was further carried out. This docking study indicated the de-unit III homologs of 2−8 did not have better binding energies than 2. As for the trimers, 3-<i>entC</i>, 3C-<i>entE</i>, 3<i>ent</i>-C, 3C, and 3<i>ent</i>, showed comparable docking score to 2. The verification of this virtual screening was partially done by evaluating the inhibitory activity of the dimeric 2-nor-<i>ent</i>, 3-nor, 3-nor-<i>ent</i>, and iso-2-nor-<i>ent</i>, isolated from peanut skins, against <i>α</i>-glucosidase. Of these, iso-2-nor-ent, the only proanthocyanidin with (2<i>β</i>→O→7, 4<i>β</i>→6) interflavane linkage, showed the best activity (IC<sub>50</sub> 9.72 <i>μ</i>M). Their simulation profiles of docking score also displayed a reasonable qualitative consistency with the overall trend of the bioassay results. This study demonstrates that virtual screening using this built model to search <i>α</i>-glucosidase inhibitors is facile and feasible and peanut skin might be used as a hypoglycemic food.
Highlights
Introduction αGlucosidase (EC 3.2.1.20), an exo-type glycosidase, can digest oligosaccharide and disaccharide by hydrolyzing the α-1, 4-glycosidic linkage to release glucose [1]
Maltase-glucoamylase (EC 3.2.1.20 & 3.2.1.3), present in human small intestinal mucosa and exerting the α-glucosidase activity, is the key enzyme involved in carbohydrate digestion and glucose absorption [2, 3]
Our study found that isovitexin 2''-(E)-p-coumarate among 17 flavonoids isolated from Tinospora crispa leaf showed the best activity against α-glucosidase with an IC50 value of 4.3 ± 1.4 μM [7]
Summary
Introduction αGlucosidase (EC 3.2.1.20), an exo-type glycosidase, can digest oligosaccharide and disaccharide by hydrolyzing the α-1, 4-glycosidic linkage to release glucose [1]. Maltase-glucoamylase (EC 3.2.1.20 & 3.2.1.3), present in human small intestinal mucosa and exerting the α-glucosidase activity, is the key enzyme involved in carbohydrate digestion and glucose absorption [2, 3]. While this enzyme is inhibited, glucose absorption will be delayed, leading to the decrease of postprandial blood glucose level [4]. Such inhibitors including acarbose (Glucobay®) and voglibose (Voglib®) have been used in clinic for the treatment of hyperglycemia in type-2 diabetes mellitus patients.
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