Study On The Inhibitory Activity Of Resveratrol And Pterostilbene On α-glucosidase And Their Druggability

Resveratrol and pterostilbene are common ingredients in many fruits and vegetables,alcoholic beverages,and currently popular dietary supplements.Their association withα-glucosidase（α-glu）is expected to explain their antidiabetic activity in various trials.In this study,the relationship between resveratrol,pterostilbene and-glucosidase activity was studied by enzyme inhibition kinetics and molecular docking simulation.The results showed that both resveratrol and pterostilbene inhibited potentlyα-glucosidase activity in a noncompetitive manner.Resveratrol had a strong inhibitory effect onα-glucosidase activity(IC₅₀=5.05±1.05μM,₄)=5.74±0.20μM),which was more petent than that of acarbose(IC₅₀=632.60±1.15μM).Pterostilbene showed moderate inhibition onα-glucosidase activity(IC₅₀=16.32±1.24μM,₄)=65.44±4.07μM).Molecular docking simulation showed that there were three possible binding sites of resveratrol,pterostilbene withα-glucosidase,all of which were far away from the binding sites of acarbose andα-glucosidase.Therefore,resveratrol and pterostilbene have the potential to be developed into hypoglycemic drugs,and can also be combined with acarbose as a dietary supplement to exert hypoglycemic effect.This study also investigated the possibility of drug-drug interactions（DDIs）due to the inhibition on the activity of UGTs enzyme by resveratrol and pterostilbene.The recombinant human UGTs enzyme was used as the enzyme source.Imipramine and 4-Methylumbelliferone were used as the probe substrates to detect the activity of UGT1A4 and other UGTs,respectively.The concentration of the product 4-Methylumbelliferyl-b-D-glucuronide detected by HPLC was used to determine the effect of resveratrol and pterostilbene on the activity of UGTs.The preliminary results showed that both resveratrol and pterostilstilum showed potent inhibition effects on UGT1A9,with IC₅₀ values of 9.23±2.66μM and 0.92±0.25μM,respectively.At the same time,resveratrol has moderate inhibitory effects on UGT1A1,UGT1A7 and UGT1A10,with an IC₅₀ value of 36.34μM-65.60μM.Pterostilbene showed moderate inhibitory effects on UGT1A1,UGT1A3,UGT1A6,UGT1A8,UGT2B15,with 17.11μM-67.51μM.Further studies showed that resveratrol strongly inhibited the activity of UGT1A9by mixed inhibition,the inhibition constant₄)value was 11.82±0.92μM.And pterostilbene strongly inhibited the activity of UGT1A9 by non-competitive inhibition,the₄)value was0.52±0.04μM.Then,the possibility of drug interaction was quantitatively predicted through the calculation formula of drug interaction combined with IVIVE method and the human pharmacokinetic data of resveratrol and pterostilbene.It is predicted that when resveratrol was taken together with drugs that were mainly metabolized by UGT1A9,the dose of resveratrol was greater than 3 g,and the AUC increment of drugs taken together was up to 20%,and there was a moderate risk of drug interactions.For pterostilbene,when the oral dose of pterostilbus is 50 mg,the AUC increment of the drug taken together will reach 20%of the risk range.At regular doses,AUC increments can be as high as 568%.Therefore,in the development and application of drugs containing resveratrol and pterostilbene,attention should be paid to their interaction with drugs mainly metabolized by UGT1A9.