Discovery of New α-Glucosidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation

Abstract

α-Glycosidase inhibitors could inhibit the digestion of carbohydrates into glucose and promote glucose conversion, which have been used for the treatment of type 2 diabetes. In the present study, 52 candidates of α-glycosidase inhibitors were selected from commercial Specs compound library based on molecular docking–based virtual screening. Four different scaffold compounds (7, 22, 37, and 44) were identified as α-glycosidase inhibitors with IC50 values ranging from 9.99 to 35.19 μM. All these four compounds exerted better inhibitory activities than the positive control (1-deoxynojirimycin, IC50 = 52.02 μM). The fluorescence quenching study and kinetic analysis revealed that all these compounds directly bind to α-glycosidase and belonged to the noncompetitive α-glycosidase inhibitors. Then, the binding modes of these four compounds were carefully investigated. Significantly, these four compounds showed nontoxicity (IC50 > 100 μM) toward the human normal hepatocyte cell line (LO2), which indicated the potential of developing into novel candidates for type 2 diabetes treatment.

Globularia alypum L. and Related Species: LC-MS Profiles and Antidiabetic, Antioxidant, Anti-Inflammatory, Antibacterial and Anticancer Potential

“…This can partially be achieved by inhibiting the activity of α-glucosidase, the key enzyme responsible for hydrolytic cleavage of complex carbohydrates. Inhibition of α-glucosidase may retard the absorption of glucose and decrease postprandial blood glucose levels and, therefore, it is one of the key targets for treating type 2 diabetes mellitus (T2DM) [ 46 ]. All four species caused significant inhibition of α-glucosidase activity at the concentrations tested (0.5 and 1.0 mg/mL) ( p < 0.05), with G. alypum extracts being most effective (30.0–45.7% inhibition) ( Figure 4 ).…”

Metabolomics-based profiling of 4 avocado varieties using HPLC–MS/MS and GC/MS and evaluation of their antidiabetic activity

“…Uncontrolled hyperglycemia is directly associated with a high risk of diabetic related complications such ischemic heart disease, stroke, and diabetic retinopathy. According to a recent estimate by the World Health Organization (WHO), more than 422 million patients suffered from diabetes worldwide in 2014 and the prevalence of the disease threatening will increase dramatically by 2040 to exceed 642 million 23 .…”

“…Unfortunately, acarbose, the first approved enzyme inhibitor suffered from unexpected side-effects such as stomach-ache, flatulence, and diarrhea 24 . Recently, the trends toward natural phytoconstituents as enzyme inhibitors have gained a special interest in many scientific studies over the synthetic hypoglycemic agents 23 , 24 . As shown in Table S2 , Gwen avocado (KG) showed the highest inhibitory activity against both α -glycosidase and α -amylase with IC 50 of 55.07 ± 2.48 and 95.3 ± 2.02 µg/ml, respectively, compared to acarbose.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part I)

“…An important aspect of diabetic homeostasis is the maintenance of glycemic control through the inhibition of α-glucosidase activity; α-glucosidase is a carbohydrate hydrolase that regulates blood sugar by hydrolyzing the 1,4-α-glucopyranosidic bond, leading to α-glucose production, hence increasing the blood sugar levels [ 163 ]. Molecular docking studies showed that the combination of oleanolic and UAs inhibited the activity of α-glucosidase by binding preferentially to different allosteric sites, interacting with surrounding amino acid residues, and disturbing the enzyme conformation, finally resulting in a decrease in α-glucosidase activity [ 164 ].…”