In Silico Docking Analysis of A-type Proanthocyanidins to α-Glucosidase Constructed by Correlation with in Vitro Bioassay

摘要

The type A proanthocyanidins (2-8) with (2β→O→7, 4β→8) interflavane linkage, isolated from Machilus philippinensis, have been found to possess inhibitory activity against α-glucosidase (EC 3.2.1.20 from Bacillus stearothermophilus). To rationalize such activity, computer assisted docking of these compounds and the positive control, acarbose, on the conformation model of α-glucosidase (AG), built by using human intestinal maltase glucoamylase as a template, was undertaken in this study. The result showed good correlation between IC_(50) values and docking scores, expressed as binding energy (ΔG), obtained from London (trimatch)-refinement (forcefield Affinity ΔG) mode. Among these isolates, the most potent aesculitannin B (2) (IC_(50) 3.5 μM) 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.e., 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-entC, 3C-entE, 3ent-C, 3C, and 3ent, 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-ent, 3-nor, 3-nor-ent, and iso-2-nor-ent, isolated from peanut skins, against α-glucosidase. Of these, iso-2-nor-ent, the only proanthocyanidin with (2β→O→7, 4β→6) interflavane linkage, showed the best activity (IC_(50) 9.72 μM). 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 α-glucosidase inhibitors is facile and feasible and peanut skin might be used as a hypoglycemic food.