Inhibitory Activity and Mechanism Investigation of Hypericin as a Novel α-Glucosidase Inhibitor.

Qi Dong,Honglun Wang,Na Hu,Huilan Yue

doi:10.3390/molecules26154566

Abstract

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC50) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10−5 M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.

Highlights

Diabetes mellitus (DM) pertains to a range of metabolic disorders that are characterized by chronic hyperglycemia, coupled with insufficiencies and/or dysfunctional insulin secretion [1]
Stock solutions of acarbose and hypericin were prepared with dimethyl sulfoxide (DMSO). pNPG was obtained from Aladdin
Using α-glucosidase inhibition experiments and enzyme kinetics study, we have shown that hypericin imparts a strong inhibitory effect on α-glucosidase, and this activity is reversible and involves competitive inhibition of α-glucosidase

Summary

Introduction

Diabetes mellitus (DM) pertains to a range of metabolic disorders that are characterized by chronic hyperglycemia, coupled with insufficiencies and/or dysfunctional insulin secretion [1]. Hyperglycemia is the most important index of all types of diabetes and can lead to various complications, such as cardiovascular disease, renal failure, neuropathy, lipid metabolism disorder, and others [3,4]. Epidemiological studies showed that postprandial hyperglycemia was an important factor leading to impaired glucose tolerance and development of type 2. Regulating postprandial blood glucose plays an important role in preventing vascular complications [5]. Maintaining postprandial blood glucose levels in a normal range is one of the important ways to control blood glucose fluctuation, which prevents the occurrence of cardiovascular and cerebrovascular diseases, and reduces the mortality of cardiovascular and cerebrovascular diseases [6]. Controlling the blood sugar level is very important for diabetics [7,8]

Methods

Results

Conclusion