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研究生:鐘千虹
研究生(外文):Chien-Hung Jhong
論文名稱:利用分子對接篩選天然物抑制α-葡萄糖苷酶與α-澱粉酶及其降低血糖之功效
論文名稱(外文):Molecular docking for screening alpha-glucosidase and alpha-amylase inhibitor from natural compounds and investigating the glycemic effect
指導教授:翁慶豐翁慶豐引用關係
指導教授(外文):Ching-Feng Weng
學位類別:碩士
校院名稱:國立東華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
論文頁數:78
中文關鍵詞:醣祿錠(Acarbose)α-葡萄糖苷酶α-澱粉酶高血糖糖尿病
外文關鍵詞:Acarboseα-glucosidaseα-amylasehyperglycemiadiabetes mellitus
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糖尿病控制血糖方式,其中α-葡萄糖苷酶抑制劑(alpha-glucosidase inhibitor)可抑制腸道α-葡萄糖苷酶(alpha-glucosidase)及胰臟α-澱粉酶(alpha-amylase),延緩碳水化合物及雙糖分解,達降血糖效果。目前臨床用藥α-葡萄糖苷酶抑制劑(Acarbose)治療長期嚴重高血糖與飯後高血糖患者,往往需增加藥物劑量或與其他降血糖藥物合併使用,常易引起低血糖的副作用。故本研究以分子對接方式篩選天然物作為降低高血糖之可行性,篩選拮抗α-葡萄糖苷酶與α-澱粉酶高活性天然化合物。47個天然化合物利用分子對接方法篩選對α-澱粉酶及α-葡萄糖苷酶有效之α-葡萄糖苷酶之抑制劑。抑制α-葡萄糖苷酶篩選結果為Curcumin和Antroquinonol。抑制α-澱粉酶篩選結果為Curcumin抑制能力較佳,其次為16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H)、Docosanol、Tetracosanol、Antroquinonol、Berberine、Catechin、Quercetin、Actinodaphnine及Rutin。使用酵素活性測定α-葡萄糖苷酶及α-澱粉酶進一步評估天然化合物抑制效果。抑制α-葡萄糖苷酶活性結果顯示Curcumin、Actinodaphnine、16-H及Quercetin比acarbose抑制效果較佳,其分別抑制α-葡萄糖苷酶活性比為36.1、15.8、15和10.7倍。α-澱粉酶抑制結果顯示Curcumin、Berberine、Docosanol、16-H及Catechin抑制效果較好,其分別抑制α-澱粉酶活性比為7.7、5.9、4.8、和3.6倍之Acarbose。以人類腸癌細胞(Caco-2)做為天然化合物篩選細胞平台,且模擬在雙醣類(麥芽糖)條件下,同時處理6、12和24小時並給予不同濃度之天然化合物,其結果表示Catechin 和 Quercetin可以減少麥芽糖被酵素分解為葡萄糖。在小鼠實驗結果,處理Acarbose、Curcumin、16-H、Docosanol、Tetracosanol、Antroquinonol、Catechin、Actinodaphnine及Rutin與對照組單一處理澱粉相比具有降血糖效果。Acarbose 比起 Curcumin、16-H、Docosanol、Tetracosanol、Antroquinonol、Catechin、Actinodaphnine及Rutin有顯著的降低老鼠血糖值。由此可知利用分子對接的方式可有效且快速篩選出天然化合物之方法,並經酵素活性、細胞及小鼠抑制血糖加以確認。
The inhibitions of alpha-glucosidase and alpha-amylase activity in the digestive tract of humans are oral anti-diabetic drug used for controlling carbohydrates digest that are normally converted to simple sugars and are absorbed by intestine. However, diabetic patients suffer from hyperglycemia after meal, the clinical medicine-Acarbose is applied for therapy with gradually increasing dosage and induced-hypoglycemic side effect. The present study aimed to find out the alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity. Molecular docking approach to reduce the hyperglycemia antagonist alpha-glucosidase and alpha-amylase activity from the 47 natural compounds. The docking data found that natural compounds include Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. In analyzed enzyme activity in test tube revealed that natural compounds of alpha-glucosidase inhibitor were Curcumin, Berberine, Docosanol, and 16-H for 36.1, 15.8, 15 and 10.7 fold as compared to Acarbose. In analyzed enzyme activity in test tube revealed that natural compounds of alpha-amylase inhibitor were Curcumin, Berberine, Docosanol, 16-H and Catechin for 7.7, 5.9, 4.8, and 3.6 fold as compared to Acarbose. For testing the inhibition of natural compounds in Caco-2 (human colonic carcinoma cell) cell line as a model of maltose conditions with different concentrations of natural compounds was performed for 6, 12 and 24 hr. Caco-2 cell line treated with Catechin and Quercetin could reduce maltose-induced glucose level. In vivo experiment showed that compared with positive control Acarbose, Curcumin, 16-H, Docosanol, Tetracosanol, Antroquinonol, Catechin, Actinodaphnine and Rutin could significantly reduce the blood glucose level in mice. And natural compounds as inhibitors of alpha-glucosidase and alpha-amylase are confirmed via the enzyme activity, in vitro and in vivo experiments. Furthermore, this implicates that molecular docking is a fast and effective way to screen lead compound of natural sources isolated from medicinal plant.
Abstract ..................................................................................................................... VII
Abbreviations ............................................................................................................ IX
Introduction .................................................................................................................. 1
Digestion of carbohydrates ...................................................................................... 1
Glycoside hydrolase family ...................................................................................... 2
Alpha-glucosidase enzyme ................................................................................... 2
Alpha-amylase enzyme ......................................................................................... 2
Diabetes mellitus (DM) ............................................................................................ 3
Prevalence of diabetes mellitus ............................................................................... 3
Pathophysiology of T2DM ....................................................................................... 3
Current medications of diabetes ............................................................................. 4
Sulfonylureas ......................................................................................................... 4
Meglitinides ........................................................................................................... 5
Biguanides ............................................................................................................. 5
Thiazolidinediones (TZD) .................................................................................... 5
Alpha-glucosidase inhibitors ............................................................................... 6
Natural compounds .................................................................................................. 7
Virtual screening of alpha-glucosidase and alpha-amylase from natural
compounds .............................................................................................................. 11
The molecular structure of the alpha-amylase ................................................ 11
The molecular structure of alpha-glucosidase ................................................. 12
Rationale and specific aims ....................................................................................... 15
Research design .......................................................................................................... 17
In silico .................................................................................................................... 17
Enzyme assay ........................................................................................................... 18
In vitro...................................................................................................................... 18
In vivo ...................................................................................................................... 18
Materials and methods .............................................................................................. 19
Screening natural compounds by molecular docking ......................................... 19
Software of molecular docking .......................................................................... 19
Filter principle .................................................................................................... 19
Screening ............................................................................................................. 20
Natural compounds ................................................................................................ 20
Acarboses solution preparation ............................................................................ 20
Determining alpha-glucosidase activity ............................................................... 21
Determining alpha-amylase activity ..................................................................... 21
Cell culture .............................................................................................................. 22
Cell viability assay .................................................................................................. 22
RNA isolation .......................................................................................................... 23
Reverse transcription polymerase chain reaction (RT-PCR) ............................ 23
Analysis of PCR products ...................................................................................... 24
Glucose assay .......................................................................................................... 24
Oral starch tolerance test (OSTT) ........................................................................ 24
Statistical Analyses ................................................................................................. 25
Results ......................................................................................................................... 27
Discussion.................................................................................................................... 33
Conclusion .................................................................................................................. 37
Future works .............................................................................................................. 39
References ................................................................................................................... 41
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