Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder in which the prevalence has been increasing steadily in worldwide. As a result, it is widespread rapidly caused by the gene, extra weight, and metabolism syndrome. The inhibition of α-glucosidase and α-amylase is an alternatively clinical treatment to delay the absorption of glucose in controlling hyperglycemia. The seeking new drugs from small molecules or natural compounds via virtual screening is crucial because the composition from some natural sources whether are targeted to the α-glucosidase and α-amylase as a hypoglycemic reagent still unexplored. The aim of the present study was to screen 53 natural compounds against α-glucosidase and α-amylase via molecular docking through Discovery Studio Visualizer version 3.5 software based on score function and docking energy. According to screened rank, ten natural compounds were selected. Further study attempted to evaluate the hypoglycemia efficacy of selected compounds via cellular and mouse levels. The results illustrated that the cytotoxicity in all tested compounds at various concentrations except the concentration of 16-hydroxy-cleroda-3,13-dine-16,15-olide (HCD) at 30 μM was not a significant difference (p> 0.05) when compared with the untreated control. Acarbose (reference drug), Antroquinonol, Catechin, Quercetin, Actinodaphnine, Curcumin, HCD, Docosanol, Tetracosanol, Berberine, and Rutin could effectively inhibit the α-glucosidase activity of Caco-2 cells when compared with the control (maltose). The compounds (Curcumin, HCD, Tetracosanol, Antroquinonol, Berberine, Catechin, Actinodaphnine, and Rutin) could reduce blood sugar level at 30 min in tested mice. The effects of tested compounds on the area under the curve (AUC) were significant (p < 0.05) among Acarbose, Tetracosanol, Antroquinonol, Catechin, Actinodaphnine, and Rutin along with Berberine and Quercetin. In in vitro (α-glucosidase) with in vivo (alpha-amylase), experiments suggest that bioactive compounds can be a potential inhibitor candidate of α-glucosidase and α-amylase for the alleviation of type II diabetes. The inhibition of glucosidase and amylase is a clinical strategy for the treatment of type II diabetes, and herbal medicines have been reported to credibly alleviate hyperglycemia. Our previous study has reported some constituents from plant or herbal sources targeted to glucosidase and amylase via molecular docking and enzymatic measurement, but the hypoglycemic potencies in cell system and mice have not been validated yet. The in vitro and in vivo studies were aimed to elucidate the hypoglycemic efficacy of docking selected compounds in cell assay and oral glucose and starch tolerance tests of mice. The result showed all test compounds could inhibit the glucosidase activity in Caco-2 cells. The OGTT and OSTT tests of mice showed the blood sugar levels of test compounds treatments were decrease significantly at 30 min and 60 min, and that varied with the effects of acarbose. Taken altogether, in vitro and in vivo experiments suggest that selected natural compounds (curcumin, antroquinonol, HCD, docosanol, tetracosanol, rutin, and actinodaphnine) via molecular docking were confirmed as potential candidates of glucosidase and amylase inhibitors for treating diabetes. Based on virtual screening data, the enzymatic assay, in vitro cell level and in vivo test are undergoing to do validate the screening results for confirming the efficacy of selected hits. This study will provide a clue for searching the hypoglycemic reagents for diabetes treatment and the new strategy for anti-diabetic drug discovery.

Chapter 1 Introduction 6
11 Diabetes mellitus (causes and prevalence) 6
12 Diagnosis of DM 7
13 Classification of DM 9
14 Treatment of DM 16
Chapter 2 Literature review 21
21 α-Glucosidase inhibitors 21
22 α-Amylase inhibitors 23
23 Virtual screening & drug discover 25
24 In silico analysis & molecular docking 26
Chapter 3 Objective 29
Chapter 4 Materials and methods 30
41 Ligand preparation 30
42 Molecular docking 30
43 Cell viability assay 32
44 Cell glucose assay 32
45 Biological assay: α-amylase activity 33
46 In vivo model: oral starch tolerance test (OSTT) 33
47 Statistical Analyses 34
Chapter 5 Results 35
51 Screening bioactive compounds 35
52 Molecular docking 36
53 Natural compounds and protein interaction with docking score function 37
54 The cytotoxicity of natural compounds on Caco-2 cells 38
55 Inhibitory α-glucosidase activity of selected natural compounds in cells 39
56 Hypoglycemic effects in oral administration of natural compounds in mice 42
Chapter 6 Discussion 43
Chapter 7 Conclusion 49
Chapter 8 Perspective 51
Chapter 9 Future work 53
Chapter 10 Reference 54
Figure Legend 84
Figure 87
Table 95
Appendix 115

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