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系統識別號 U0026-2708202015080200
論文名稱(中文) 利用虛擬篩選來檢視小分子化合物在FGF9 5'UTR以及IRES接合位的對接
論文名稱(英文) To examine the chemical compounds docking on FGF9 RNA 5'UTR and IRES binding site by using virtual screening
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 108
學期 2
出版年 109
研究生(中文) 楊正
研究生(英文) Cheng Yang
學號 T16061053
學位類別 碩士
語文別 英文
論文頁數 41頁
口試委員 指導教授-孫孝芳
口試委員-林世杰
口試委員-陳琮明
中文關鍵字 人類纖維母細胞生長因子  缺氧  小分子藥物 
英文關鍵字 FGF9  Hypoxia  Small molecular compounds 
學科別分類
中文摘要 我們實驗室先前的研究發現人類纖維母細胞生長因子(FGF9)在缺氧的環境下會透過非傳統Internal Ribosome Entry Site (IRES)-參與轉譯機制的調節來提高FGF9蛋白質的表達。並且, FGF9蛋白質被大量表達在大腸直腸細胞癌化扮演重要的角色是因此本研究假設如果利用小分子藥物來阻擋FGF9 IRES參與轉譯的機制,也許可以達到抑制FGF9蛋白質在大腸直腸癌細胞大量表達的目的。然而,想要利用新藥開發的方式來找到特定可以抑制IRES參與的轉譯調節機制的小分子藥物是一個非常消耗時間與金錢方法。因此,本研究擬利用Discover Studio的軟體來進行小分子藥物與FGF9 mRNA對接的模擬,試圖從中找到能夠與FGF9 mRNA的5’UTR及IRES位置有效結合並抑制轉譯反應進行的小分子藥物,以達到癌症抑制的效果。我們利用Discovery Studio中CDOCKER的方法分析了美國食品藥物管理局 (FDA)核准用藥的資料庫以及美國國家癌症研究中心 (National Cancer Institute; NCI)癌症用藥資料庫用於對接分析的小分子化合物。在本篇論文中將針對分子對接的模擬分析來試圖從中找到可供進一步研究的小分子化合物。
英文摘要 Our lab previously published that overexpression of FGF9 protein is happened when the tumor cells under hypoxia pressure. Also, the mechanism of FGF9 protein overexpression is found through non-canonical IRES-mediated translation. However, it is a time-consuming and costly approach to go through new drug development and to find the specific small molecular drugs to inhibit FGF9 IRES-mediated translation. Therefore, we conducted a high-throughput screening in this research to dock the small molecular compounds and FGF9 mRNA 5’UTR and IRES predicted binding sites by using Discovery Studio software in order to find the small molecular compounds which are able to inhibit FGF9 IRES-mediated translation. We analyze the FDA-approved drug database and NCI database by using CDOCKER program from Discovery Studio. In this research, our objective is using the CDOCKER program from Discovery Studio to select the small molecular candidates for further study.
論文目次 中文摘要 .......................................... 2
Abstract .......................................... 3
Table of Contents ................................. 4
1 Introduction
1.1 IRES-mediated translational activation..... 8
1.2 IRES-mediated FGF9 overexpression is involved in cancer cells translation under hypoxia............................................ 9
1.3 Small molecular drug development .......... 10
1.4 Hypothesis and objective of this study..... 11
1.5 Specific aims.................................. 11
2. Material and Methods
2.1 Drug databases used during conducting virtual screening experiment............ 12
2.1.1 Approved Drug Database...................................................... 12
2.1.2 NCI Database.................................................................13
2.2 In Silico Docking Screening ...................................................13
2.3 Ligand and receptor preparation............................................... 13
2.4 Docking ...................................................................... 13
2.5 CDOCKER....................................................................... 14
2.6 Scoring function and Ranking ................................................. 14
2.7 Scoring function and Ranking.................................................. 15

3. Results
3.1 FGF9 2D and 3D predicted Structure............................................ 17
3.2 FGF9 predicted binding sites.................................................. 17
3.2.1 NCI Database Docking Results................................................ 17
3.2.2 Approved Drug Database Scoring and Ranking.................................. 17
4. Discussion .................................................................... 19
5. Reference...................................................................... 21
6. Figures ....................................................................... 26
7. Tables ........................................................................31
參考文獻 1. Anne-Claude Gingras, a. Brian Raught and N. Sonenberg (1999). "eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation." Annual Review of Biochemistry 68(1): 913-963.
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19. Mattei, M. G., F. Penault-Llorca, F. Coulier and D. Birnbaum (1995). "The human FGF9 gene maps to chromosomal region 13q11-q12." Genomics 29(3): 811-812.
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24. Tsai, S. J., M. H. Wu, H. M. Chen, P. C. Chuang and L. Y. Wing (2002). "Fibroblast growth factor-9 is an endometrial stromal growth factor." Endocrinology 143(7): 2715-2721.
25. Utecht, K. N. and J. Kolesar (2008). "Bortezomib: A novel chemotherapeutic agent for hematologic malignancies." American Journal of Health-System Pharmacy 65(13): 1221-1231.
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21. Lobanov, V. (2004). "Using artificial neural networks to drive virtual screening of combinatorial libraries." Drug Discovery Today: BIOSILICO 2(4): 149-156.
22. Majumder, M., I. Yaman, F. Gaccioli, V. V. Zeenko, C. Wang, M. G. Caprara, R. C. Venema, A. A. Komar, M. D. Snider and M. Hatzoglou (2009). "The hnRNA-binding proteins hnRNP L and PTB are required for efficient translation of the Cat-1 arginine/lysine transporter mRNA during amino acid starvation." Mol Cell Biol 29(10): 2899-2912.
23. Martínez-Salas, E., G. Lozano, J. Fernandez-Chamorro, R. Francisco-Velilla, A. Galan and R. Diaz (2013). "RNA-binding proteins impacting on internal initiation of translation." Int J Mol Sci 14(11): 21705-21726.
24. Mattei, M. G., F. Penault-Llorca, F. Coulier and D. Birnbaum (1995). "The human FGF9 gene maps to chromosomal region 13q11-q12." Genomics 29(3): 811-812.
25. Miyamoto, M., K. Naruo, C. Seko, S. Matsumoto, T. Kondo and T. Kurokawa (1993). "Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property." Mol Cell Biol 13(7): 4251-4259.
26. Ou-Yang, S. S., J. Y. Lu, X. Q. Kong, Z. J. Liang, C. Luo and H. Jiang (2012). "Computational drug discovery." Acta Pharmacol Sin 33(9): 1131-1140.
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30. Tsai, S. J., M. H. Wu, H. M. Chen, P. C. Chuang and L. Y. Wing (2002). "Fibroblast growth factor-9 is an endometrial stromal growth factor." Endocrinology 143(7): 2715-2721.
31. Utecht, K. N. and J. Kolesar (2008). "Bortezomib: A novel chemotherapeutic agent for hematologic malignancies." American Journal of Health-System Pharmacy 65(13): 1221-1231.
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33. Wang, Y., S. Zhang, F. Li, Y. Zhou, Y. Zhang, Z. Wang, R. Zhang, J. Zhu, Y. Ren, Y. Tan, C. Qin, Y. Li, X. Li, Y. Chen and F. Zhu (2019). "Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics." Nucleic Acids Research.
34. Wishart, D. S., Y. D. Feunang, A. C. Guo, E. J. Lo, A. Marcu, J. R. Grant, T. Sajed, D. Johnson, C. Li, Z. Sayeeda, N. Assempour, I. Iynkkaran, Y. Liu, A. Maciejewski, N. Gale, A. Wilson, L. Chin, R. Cummings, D. Le, A. Pon, C. Knox and M. Wilson (2017). "DrugBank 5.0: a major update to the DrugBank database for 2018." Nucleic Acids Research 46(D1): D1074-D1082.
35. Wouters, B. G. and M. Koritzinsky (2008). "Hypoxia signalling through mTOR and the unfolded protein response in cancer." Nat Rev Cancer 8(11): 851-864.
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