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研究生：	陳博晉 Po-Chin Chen
論文名稱：	以熱力學積分分子動力學模擬方法計算細胞外信號調節激酶與其抑制劑的結合自由能 Computation of Binding Free Energy of Inhibitor-Erk Kinase Complexs Using Thermodynamic Integration Molecular Dynamics Simulation
指導教授：	孫英傑 Sun, Ying-Chieh
學位類別：	碩士 Master
系所名稱：	化學系 Department of Chemistry
論文出版年：	2012
畢業學年度：	100
語文別：	中文
論文頁數：	58
中文關鍵詞：	分子動力學模擬、自由能、細胞外信號調節激酶、熱力學積分
英文關鍵詞：	Molecular Dynamics Simulation, Free Energy, Extracellular signal-regulated kinases, Thermodynamic Integration
論文種類：	學術論文
相關次數：	點閱：101 下載：1
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Erk激酶是Ras/Raf/MEK/ERK 訊號傳遞路徑的下游蛋白質，此路徑在某些癌症當中失調。我們選擇此蛋白質激酶並且使用分子動力學模擬來設計此蛋白質激酶新的抑制劑。先前的計算當中發現熱力學積分分子動力學模擬方法於計算蛋白質激酶一組抑制劑得到的相對自由能與實驗結果相近。在目前的研究上我們對新的類似化合物進行TI-MD計算是為了要搜尋出更好的抑制劑。一個在苯環上帶有OH官能基的類似物被發現比82A有更好的親和性約1.1千卡/莫耳。除此之外，我們探討於TI-MD方法中一步變換與三步變換上的表現之比較。另外，也討論關於不同的λ數目在計算上對於相對自由能上的影響。這些結果應該會對於未來TI-MD模擬以及這種類的抑制劑之設計會有一些幫助。

Erk is the downstream protein in the Ras/Raf/MEK/ERK signal transduction pathway which is deregulated in many cancers. In the present study, we select this kinase to design new inhibitors for this kinase using MD simulation. Previous computations have shown that thermodynamic integration (TI) MD simulation method is able to give relative binding free energy for a pair of inhibitors for this kinase in good agreement with experimental results. In the present study, we carried out TI-MD computations for new analogous compounds in searching for better inhibitors. An analog with –OH functional group on the benzene ring was found to have better affinity than the 82A ligand by 1.1 kcal/mol. In addition, we investigate how single mutational step performs compared with the triple mutational steps in the TI-MD method. Furthermore, effect of number of lambda points in the computed relative binding free energy was investigated as well. These results should be useful for further TI-MD simulation and inhibitor design of this kind.

口試委員會審定書    #
謝誌    i
中文摘要    ii
ABSTRACT    iii
目錄(CONTENTS)    iv
圖表目錄 (LIST OF FIGURES)    vi
表格目錄(LIST OF TABLES)    viii
Chapter 1    緒論 (Introduction)    1
1.1    前言 (Preface)    1
1.1.1    藥物開發(Drug development)    1
1.2    ERK 蛋白質激酶與癌症的關聯(The Relationship Between ERK Protein Kinase and Cancer)    4
1.3    研究目標(Research Objectives)    8
Chapter 2    實驗方法 (Experimental Methods)    10
2.1    實驗理論 (Theories)    10
2.1.1 分子動力學模擬 (Molecular Dynamics Simulation)    10
2.1.2 分子動力學模擬理論 (Molecular Dynamics simulation theory)    10
2.1.3 參數組 (Parameter set)    12
2.1.4 應用程式 (Application)    14
2.1.5 熱力學積分 (Thermodynamic Integration, TI)    15
2.2    實驗設定 (Modeling Settings)    18
2.2.1    分子動力學模擬設定 (Molecular Dynamics Simulation settings )    18
2.2.2    RESP (Restrained electrostatic potential)    19
2.2.3    Functional group transformation    20
2.2.4    Cheng-Prusoff equation    20
2.2.5    TTA v.s. STA    23
2.2.6    Comparison of different λ points    24
Chapter 3    結果與討論 (Results and Discussions)    25
3.1    TTA (Three transformation approach) relative binding free energy( λ points = 9)    25
3.1.1    TTA：CFO to 82A (solution phase)    25
3.1.2    TTA：CFO to 82A (complex phase)    27
3.1.3    Summary of CFO to 82A    32
3.2    Comparison of TTA with STA    33
3.2.1    Results of STA (CFO to 82A)    33
3.3    Result of different λ points in TTA    39
3.3.1    λ points equal to 9    39
3.3.2    λ points equal to 5    42
3.3.3    λ points equal to 4    45
3.4    Difference between each lambda points    49
Chapter 4    結論 (Concluding Remark)    52
英文專有名詞中文翻譯    54
參考文獻(Reference)    56

                                

1. Munos, B., Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 2009, 8 (12), 959-968.
2. Corey, E.; Long, A.; Rubenstein, S., Computer-assisted analysis in organic synthesis. Science 1985, 228 (4698), 408-418.
3. Gil L., A.; Valiente, P. A.; Pascutti, P. G.; Pons, T., Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design. Journal of Tropical Medicine 2011, 2011.
4. Cohen, P., The development and therapeutic potential of protein kinase inhibitors. Current Opinion in Chemical Biology 1999, 3 (4), 459-465.
5. Zeevaart, J. G.; Wang, L. G.; Thakur, V. V.; Leung, C. S.; Tirado-Rives, J.; Bailey, C. M.; Domaoal, R. A.; Anderson, K. S.; Jorgensen, W. L., Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations. Journal of the American Chemical Society 2008, 130 (29), 9492-9499.
6. Mitchell, M. J.; McCammon, J. A., Free energy difference calculations by thermodynamic integration: Difficulties in obtaining a precise value. Journal of Computational Chemistry 1991, 12 (2), 271-275.
7. (a) Wang, J.; Morin, P.; Wang, W.; Kollman, P. A., Use of MM-PBSA in Reproducing the Binding Free Energies to HIV-1 RT of TIBO Derivatives and Predicting the Binding Mode to HIV-1 RT of Efavirenz by Docking and MM-PBSA. Journal of the American Chemical Society 2001, 123 (22), 5221-5230; (b) Sadiq, S. K.; Wright, D. W.; Kenway, O. A.; Coveney, P. V., Accurate Ensemble Molecular Dynamics Binding Free Energy Ranking of Multidrug-Resistant HIV-1 Proteases. Journal of Chemical Information and Modeling 2010, 50 (5), 890-905.
8. Jorge, M.; Garrido, N. M.; Queimada, A. n. J.; Economou, I. G.; Macedo, E. n. A., Effect of the Integration Method on the Accuracy and Computational Efficiency of Free Energy Calculations Using Thermodynamic Integration. Journal of Chemical Theory and Computation 2010, 6 (4), 1018-1027.
9. Masukawa, K. M.; Kollman, P. A.; Kuntz, I. D., Investigation of Neuraminidase-Substrate Recognition Using Molecular Dynamics and Free Energy Calculations. Journal of Medicinal Chemistry 2003, 46 (26), 5628-5637.
10. (a) Aronov, A. M.; Baker, C.; Bemis, G. W.; Cao, J.; Chen, G.; Ford, P. J.; Germann, U. A.; Green, J.; Hale, M. R.; Jacobs, M.; Janetka, J. W.; Maltais, F.; Martinez-Botella, G.; Namchuk, M. N.; Straub, J.; Tang, Q.; Xie, X., Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors‡. Journal of Medicinal Chemistry 2007, 50 (6), 1280-1287; (b) Massova, I.; Kollman, P., Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspectives in Drug Discovery and Design 2000, 18 (1), 113-135.
11. McCubrey, J. A.; Steelman, L. S.; Chappell, W. H.; Abrams, S. L.; Wong, E. W.; Chang, F.; Lehmann, B.; Terrian, D. M.; Milella, M.; Tafuri, A.; Stivala, F.; Libra, M.; Basecke, J.; Evangelisti, C.; Martelli, A. M.; Franklin, R. A., Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochimica et biophysica acta 2007, 1773 (8), 1263-84.
12. Sebolt-Leopold, J. S.; Herrera, R., Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004, 4 (12), 937-947.
13. Kohno, M.; Pouyssegur, J., Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Progress in cell cycle research 2003, 5, 219-24.
14. Chang, F.; Steelman, L. S.; Shelton, J. G.; Lee, J. T.; Navolanic, P. M.; Blalock, W. L.; Franklin, R.; McCubrey, J. A., Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). International journal of oncology 2003, 22 (3), 469-80.
15. Dhillon, A. S.; Hagan, S.; Rath, O.; Kolch, W., MAP kinase signalling pathways in cancer. Oncogene 0000, 26 (22), 3279-3290.
16. Kohno, M.; Pouyssegur, J., Targeting the ERK signaling pathway in cancer therapy. Annals of Medicine 2006, 38 (3), 200-211.
17. Hancock, C. N.; Macias, A.; Lee, E. K.; Yu, S. Y.; MacKerell, A. D.; Shapiro, P., Identification of Novel Extracellular Signal-Regulated Kinase Docking Domain Inhibitors. Journal of Medicinal Chemistry 2005, 48 (14), 4586-4595.
18. Aronov, A. M.; Tang, Q.; Martinez-Botella, G.; Bemis, G. W.; Cao, J.; Chen, G.; Ewing, N. P.; Ford, P. J.; Germann, U. A.; Green, J.; Hale, M. R.; Jacobs, M.; Janetka, J. W.; Maltais, F.; Markland, W.; Namchuk, M. N.; Nanthakumar, S.; Poondru, S.; Straub, J.; ter Haar, E.; Xie, X., Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control. Journal of Medicinal Chemistry 2009, 52 (20), 6362-6368.
19. Canagarajah, B. J.; Khokhlatchev, A.; Cobb, M. H.; Goldsmith, E. J., Activation Mechanism of the MAP Kinase ERK2 by Dual Phosphorylation. Cell 1997, 90 (5), 859-869.
20. Pearson, G.; Robinson, F.; Beers Gibson, T.; Xu, B.-e.; Karandikar, M.; Berman, K.; Cobb, M. H., Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions. Endocrine Reviews 2001, 22 (2), 153-183.
21. Zhang, J.; Zhang, F.; Ebert, D.; Cobb, M. H.; Goldsmith, E. J., Activity of the MAP kinase ERK2 is controlled by a flexible surface loop. Structure 1995, 3 (3), 299-307.
22. Steinbrecher, T.; Joung, I.; Case, D. A., Soft-core potentials in thermodynamic integration: Comparing one- and two-step transformations. Journal of Computational Chemistry 2011, 32 (15), 3253-3263.
23. Genheden, S.; Nilsson, I.; Ryde, U., Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA. Journal of Chemical Information and Modeling 2011, 51 (4), 947-958.
24. Cornell, W.; Cieplak, P.; Bayly, C.; Gould, I.; Merz, K.; Ferguson, D.; Spellmeyer, D.; Fox, T.; Caldwell, J.; Kollman, P., A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 1995, 117 (3), 5179-5197.
25. Case, D.; Darden, T. A.; Cheatham, T. E.; Simmerling, C.; Wang, J.; Duke, R.; Luo, R.; Crowley, M.; Walker, R.; Zhang, W.; Merz, K. M.; Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Wu, X.; Brozell, S.; Steinbrecher, T.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Kollman, P., Amber 11.
26. Michel , J.; Foloppe, N.; Essex, J. W., Rigorous Free Energy Calculations in Structure-Based Drug Design. Molecular Informatics 2010, 29 (8-9), 570-578.
27. Buelens, F. P.; Grubmüller, H., Linear-scaling soft-core scheme for alchemical free energy calculations. Journal of Computational Chemistry 2012, 33 (1), 25-33.
28. Woods, R. J.; Chappelle, R., Restrained electrostatic potential atomic partial charges for condensed-phase simulations of carbohydrates. Theochem-J. Mol. Struct. 2000, 527, 149-156.
29. Yung-Chi, C.; Prusoff, W. H., Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochemical Pharmacology 1973, 22 (23), 3099-3108.
30. Steinbrecher, T.; Mobley, D.; Case, D., Nonlinear scaling schemes for Lennard-Jones interactions in free energy calculations. J. Chem. Phys. 2007, 127 (21), 214108.
31. Darden, T.; Perera, L.; Li, L.; Pedersen, L., New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations. Structure 1999, 7 (3), R55-R60.

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