(3.238.7.202) 您好!臺灣時間:2021/03/01 21:31
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:李宣以
研究生(外文):Hsuan-Yi Li
論文名稱:以Dipeptidyl Peptidase 4 (DPP4)為標靶 自中草藥分子資料庫探索降血糖藥物
論文名稱(外文):Discovery of Hypoglycemic Agents From Traditional Chinese Medicine (TCM) Database Through Targeting Human Dipeptidyl Peptidese 4 (DPP 4)
指導教授:宣大衛宣大衛引用關係
指導教授(外文):David Shiuan
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:2014
畢業學年度:103
論文頁數:53
中文關鍵詞:降血糖糖尿病中草藥
外文關鍵詞:DPP4diebetetraditional medicine
相關次數:
  • 被引用被引用:0
  • 點閱點閱:234
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:7
  • 收藏至我的研究室書目清單書目收藏:0
糖尿病為國人十大死因之前五名,本研究以第二型糖尿病為目標,自中草藥為資料庫,致力研發新治療藥物或尋找天然食材成份,來達到治療及預防疾病之用。目前,治療糖尿病相關的口服藥物有五大類,包括:dipeptidyl piptidase-4 (DPP4)inhibitor。DPP4廣泛分佈於人體各組織中,經由切割dipeptide,而有多種功能。DPP4在腸道之主要功能為分解腸泌素GLP-1 (glucagon-like peptide),即是調控血糖平衡重要的激素。若GLP-1被分解,失去調控血糖之能力,將導致體內葡萄糖無法正常調控,而衍生出糖尿病末期因血糖控制不佳之後遺症。因此,DPP4成為研發治療糖尿病藥物之重要標靶,而DPP4 inhibitor已發現為治療二期糖尿病之有效藥物。近年來,因生物資訊學及結構生物學的進步,使得電腦輔助藥物設計蓬勃發展。電腦輔助藥物設計可以快速篩選出對受體分子結合能力強的小分子,與傳統藥物篩選不同,只需有標靶蛋白之3D structure、ligand之3D資料庫與電腦軟體,即可進行快速篩選,再經過一系列過濾,選出可能有效果的compound,再進行生物實驗。本研究利用Dicovery Studio軟體,針對DPP4進行分子對接 (docking),最後篩選出六個天然物分子,分別來自白茅根、鉤藤、育亨賓、黃柏、黃連、太白蔥木。未來將取得compound,進行生物實驗,期望能成為副作用更低,有潛力抑制DPP4之藥物。
Diabetes has been one of the top five leading causes of death in Taiwan. The present study aimed to develop new therapeutic drugs or natural ingredients as supplement for the treatment and prevention of type II diabetes. Currently, the diabetes-related oral drugs can be classified into five categories including dipeptidyl peptidase-4 (DPP4) inhibitors. DPP4 has been widely distributed in human tissues and cell. Through cleaving dipeptides, DPP4 performs a variety of physiological functions. The main function of DPP4 in human guts is to cleave GLP-1 (glucagon-like peptide-1), the most important hormone which regulating blood sugar level. If GLP-1 lost its function, severe syndromes will be developed at the late stage of diabetes. Therefore, DPP4 has become an important target for the development of drugs against type II diabetes .
  In recent years, the advances in bioinformatics and structural biology have made the computer-aided drug design (computer aided drug design) feasible. We employed high-throughput virtual screening (in silico) approach, using DPP4 as molecular target, to screen for novel drug candidates from the TCM (Traditional Chinese Medicine) database. Finally, we selected six molecule, originally isolated from Aralia taibaiensis, Imperata cylindrical, Pausinystalia yohimbe, Coptis chinensis Franch, Uncaria rhynchophylla and Phelloendron amurense. Through further DPP4 inhibition experimental studies, it is anticipated that they may have the potential to become drug candidates against type II diabetes.

致謝……………………………………………………………...…....…….II
目錄………………………………………………………………...……...III
中文摘要....………………………………...……………………………..V
英文摘要……………………………………...…………………………..VI
壹、研究目的及策略…………………………………………………...…..1
貳、研究背景………………………………………………………...…......2
1. 糖尿病之致病原因……………………………………….…………………..2
2. 腸泌素與GLP-1…………………………………………………......4
3. Dipeptidyl piptidase-4 (DPP-4)……………………………………..8
4. 電腦輔助藥物設計………………………………………………….10
5. 蛋白質資料庫 (Protein Data Bank, PDB)………………..……..12
6. 小分子資料庫 (Traditional Chinese Medicine, TCM)……………....12
7. 蛋白質及結構分析軟體(Discovery Studio, DS)………………..13
8. ADMET及其預測軟體…………………………………………..…14
參、研究方法與設備…………………………………………………………………...17
1. 研究儀器設備……………………………………………………………….17
2. 研究方法…………………………………………………………………….18
A. 蛋白質與小分子資料庫之結構處理……………………...…………..18
B. 以Discovery Studio 3.5軟體進行分子對接……………………….….19
C. Docking結果之再處理.……………………..………………….20
D. ADMET descriptor程序.…………………………….……………….21
E. 追溯篩選出小分子之植物來源與相關藥效功能…………22
F. 分析Ligand小分子與DPP4 binding site之相互作用………………..23
肆、結果……………………………………………………………………………..….25
1. 挑選DPP-4之3D結構作為Docking標靶…………………………...……..25
2. DS虛擬篩選結果-初步與精確篩選結果….…...……….…………..25
3. 選出小分子之簡要說明……………………………………………………26
4. 選出小分子之植物根源及相關藥效與功用之詳細說明………………….27
5. 候選抑制分子之ADMET預測……………………………………….…….29
6. 候選抑制分子與DPP4之交互作用分析…………………………………...35
伍、討論與未來展望…………………………………………………………………...37
陸、參考文獻……………...……………………………………………………………38
柒、圖表………………………………………………………………………………..40

Abbott CA, Baker E, Sutherland GR. Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics (1994) 40: 331-338.

Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. International Journal of Clinical Practice (2006) 60: 1454-1470.

Chen CY. The world’s largest traditional Chinese medicine database for drug screening in silico. PLOS One (2011) 6: e15939

Drucker DJ. Glucagon-like Peptide 2. Trends in Endocrinology & Metabolism (1999) 10: 153-156.

Fan Y, Guo DY, Song Q, Li T. Effect of total saponin of aralia taibaiensis on proliferation of leukemia cells. Journal of Chinese Medicinal Materials (2013) 36: 604-607.

Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regulatory Peptides (2006) 137: 147-155.

Misumi Y, Hayashi Y, Arakawa F, Ikehara Y. Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface. Biochimica et Biophysica Acta (1992) 1131: 333-336.

Tanaka T, Camerini D, Seed B, Torimoto Y, Dang N, Kameoka. Cloning and functional expression of the T cell activation antigen CD26. Journal of Immunology (1992) 149: 481-486.

Raj VS, Mou H, Smits SL. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature (2013) 495: 251-254.

Rester U. From virtuality to reality-virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective. Current Opinion in Drug Discovery & Development (2008) 11: 559 568.
Thomsen J, Kristiansen K, Brunfelft K, Sundby F. The amino acid sequence of human glucagon. FEBS Letters (1972) 21: 315-319.

Weng Y, Yu L, Cui J, Zhu YR. Antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis in experimental type 2 diabetic rats. Journal of Ethnopharmacology (2014) 152: 553-560.

Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Research (2005) 65: 1325-1334.

Yoshida T, Akahoshi F, Sakashita H, et al. Discovery and preclinical profile of teneligliptin(3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorganic & Medicinal Chemistry (2012) 20: 5705-5719.

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊
 
系統版面圖檔 系統版面圖檔