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研究生: 王文宏
論文名稱: Celebrex衍生物—PDK1抑制劑—的三維定量構效關係研究
指導教授: 孫英傑
學位類別: 碩士
Master
系所名稱: 化學系
Department of Chemistry
論文出版年: 2006
畢業學年度: 94
語文別: 中文
論文頁數: 50
中文關鍵詞: CelebrexPDK1抑制劑三維定量構效關係
論文種類: 學術論文
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  • 本論文中以celebrex為基礎的PDK1抑制劑進行比較分
    子場分析法(CoMFA)之三維定量構效關係(3D-QSAR)研究。
    使用Gaussian98套裝軟體進行量子化學計算以獲得化合物的
    結構。將這些化合物分群進行CoMFA計算得到相關數值q2介
    於0和0.8之間。其中有些q2值較低可能主要是由於生物活性
    範圍選擇不夠廣所造成。在化合物個數介於11到16之間的幾
    組計算中得到的q2值介於0.5和0.8。高q2值的計算結果可提供
    這些化合物進行化學修飾的方向以增進其生物活性,並且對
    未來以celebrex為基礎的抗癌藥物設計有所幫助。

    總目錄 圖目錄 III 表目錄-----------------------------------------------V 中文摘要---------------------------------------------VI 英文摘要---------------------------------------------VII 目錄 Celebrex衍生物—PDK1抑制劑—的三維定量構效關係研究 第一章、緒論----------------------------------------1 1-1 前言-------------------------------------------2 1-2 研究動機----------------------------------------3 1-3 PI3K/Akt信號通路(signaling pathway)與癌細胞、腫瘤的關係--6 1-4 非類固醇抗炎藥物(Non-steroidal Anti-inflammatory Drugs, NSAIDs)--------------------------------------------8 1-5 三維定量構效關係(3D-Quantitative Structure-Activity Relationship, 3D-QSAR)----------10 1-6 研究目標----------------------------------------12 第二章、理論及方法-----------------------------------13 2-1 參數法3(Parametric Method 3, PM3)--------------14 2-2 分子之穩定結構計算-------------------------------16 2-3 .Tripos力場能量最小化(Tripos Force Field Minimization)--------------------------------------17 2-4 比較分子場分析(Comparative Molecular Field Analysis, CoMFA)-----------------------------------19 2-4.1 分子排列(Molecular Alignment, Superimpose) ---------------------------------------------21 2-4.2 晶格(Lattice)--------------------------------22 2-4.3 部分最小平方法(Partial Least Square, PLS)--23 2-4.4 交叉驗證(Cross-validation)----------------------24 第三章、計算結果與討論--------------------------------26 3-1 計算所得之化合物結構---------------------------------27 3-2 .CoMFA計算的結果:q2與IC50值及討論---------------29 3-3 空間與靜電分佈圖(Steric and Electrostatic Contour Map)--------------------------------------------41 第四章、結論-------------------------------------46 第五章、參考文獻---------------------------------48 圖目錄 圖1-2 ATP與PDK1形成氫建---------------------------------3 圖1-3 PI3K-Akt的信號通路調控模型------------------------6 圖2-4 比較分子場分析程序---------------------------------20 圖2-2.3 交叉驗證法程序------------------------------------25 圖3-1.1 化合物35兩雙面角雙重掃描之後相對能量圖---------------27 圖3-1.2 化合物35經PM3結構最佳化後的結構-----------------28 圖3-2.1 PM3最佳化的結構,使用在CoMFA計算得到最好q2值----30 圖3-2.2 (a)37個化合物分子相同部分的結構圖(b)11個分子 (0~6,20,23,34~35)的空間重疊圖-----------------------31 圖3-2.3 預測IC50值(Calculated IC50)與實際IC50(Experimental IC50)的相關圖-------------------------------------32 圖3-2.4 G-A在不同位置重疊(PM3結構,M3 Mulliken電荷)--------34 圖3-2.5 化合物0~24在不同位置重疊(PM3結構,M3 Mulliken電荷) --------------------------------35 圖3-2.6 依據取代官能基分為三群:G-1A(0~6,20)、G-1B(9~19)和 G-1C(7~8,21~24)----------------------------------37 圖3-2.7 不同分子個數的空間與靜電分佈圖(PM3結構,PM3 Mulliken電荷)---------------------------------39 圖3-2.8 化合物22、23和24的PM3結構重疊---------------40 圖3-3 11個化合物(0~6,20,23,34~35)CoMFA的空間與靜電分佈圖----41 表目錄 表1-2 Celebrex及其36個衍生物對PDK1或PC-3細胞系的抑制活性-----4 表3-2.1 11個化合物(0~6,20,23,34~35)的CoMFA結果---------32 表3-2.2 預測(計算)IC50值與實際(觀察)IC50值-------------33 表3-3.1 化合物0~24的結構與PDK1 IC50值-------------------43 表3-3.2 化合物25~36的結構與PDK1 IC50值----------------45

    1. Charles Reynolds, Drugs By Design, Chemical & Engineering News, 2005; 83, 28.

    2. P. Charifson, I.D. Kuntz, Recent Successes and Continuing Limitations in Computer-Aided Drug Design, Practical Application of Computer-Aided Drug Design, 1997, 1.

    3. Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS., The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2, J. Biol. Chem. 2000; 275, 11397.

    4. Johnson AJ, Song X, Hsu A, Chen C., Apoptosis signaling pathways mediated by cyclooxygenase-2 inhibitors in prostate cancer cells., Adv. Enzyme Regul., 2001; 41,221.

    5. Song X, Lin HP, Johnson AJ, Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells., J. Natl. Cancer Inst., 2002; 94, 585.

    6. Kulp SK, Yang YT, Hung CC, PDK-1/Akt signaling represents a major COX-2 independent target for celecoxib in prostate cancer cells. Cancer Res., 2004; 64, 1444.

    7. Biondi, R.M., Komander, D., Thomas, C.C., Lizcano, J.M., Deak, M., Alessi, D.R., Van Aalten, D.M.F., High Resolution Crystal Structure of the Human Pdk1 Catalytic Domain Defines the Regulatory Phosphopeptide Docking Site., Embo J., 2002 ; 21, 4219.

    8. Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK, Chen CS., From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors., Cancer Res., 2004; 64(12), 4309.

    9. M. Osaki, M. Oshimura and H. Ito, PI3K-Akt pathway: Its functions and alterations in human cancer, Apoptosis, 2004; 9(6), 667.

    10. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N., Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol., Cancer Res., 2003; 63, 2139.

    11. Grossman HB, Selective COX-2 inhibitors as chemopreventive and therapeutic agents., Drugs Today, 2003; 39(3), 203.

    12. Toki A.T. and Masferrer J.L., Celecoxib: a specific COX-2 inhibitor with anticancer properties., Cancer Control., 2002; 9(2 Suppl), 28.

    13. Needleman P, Isakson PC., The discovery and function of COX-2., J Rheumatol, 1997; 24(Suppl 49), 6.

    14. Steinbach G, Lynch PM, Phillips RK, The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis., N. Engl. J. Med., 2000; 342(26), 1946.

    15. Koehne CH, Dubois RN., COX-2 inhibition and colorectal cancer., Semin Oncol., 2004; 31(2 Suppl 7), 12.

    16. Arun B, Goss P., The role of COX-2 inhibition in breast cancer treatment and prevention., Semin Oncol., 2004; 31(2 Suppl 7), 22.

    17. Sandler AB, Dubinett SM., COX-2 inhibition and lung cancer., Semin Oncol., 2004; 31(2 Suppl 7), 45.

    18. Sabichi AL, Lippman SM, COX-2 inhibitors and other nonsteroidal anti inflammatory drugs in genitourinary cancer., Semin Oncol., 2004; 31(2 Suppl 7), 36.

    19. Crum-Brown, A. & Frazer, T., On the connection between chemical constitution and physiological action. Part 1. On the physiological action of the ammonium bases, derived from Strychia, Brucia, Thebaia, Codeia, Morphia, and Nicotia., Transactions of the Royal Society of Edinburgh, 1868-9; 25, 151.

    20. Hansch, C., A Quantitative Approach to Biochemical Structure-Activity Relationships., Accounts of Chemical Research, 1969; 2, 232.

    21. Simon, Z.; Badileuscu, I.; Racovitan, T. J. Theor. Biol. 1977; 66, 485. Simon, Z.; Dragomir, N.; Plauchithiu, M. G.; Holban, S.; Glatt, H.; Kerek, F., Eur. J. Med. Chem., 1980; 15, 521.

    22. Hopfinger, A. J., J. Am. Chem. SOC. 1980; 102, 7196.

    23. Chose, A. K., Crippen, G. M., J. Med. Chem. 1985; 28, 333.

    24. Cramer, R. D., Milne, M., Abstracts of the ACS Meeting, April 1979, COMP 44. Wise, M., Cramer, R. D., Smith, D. M., Exman, I., Quantitative Approaches to Drug Design; Dearden, J. C., Ed.; Elsevier: Amsterdam, 1983, 145. Wise, M., Molecular Graphics and Drug Design; Burgen, A. S. V., Roberts, G. C. K., Tute, M. S., Elsevier: New York, 1986, 183. Cramer, R. D., Bunce, J. D., QSAR in Drug Design and Toxicology; Hadzi, D., Jerman-Blazic, B., Eds.; Elsevier: New York, 1987, 3.

    25. Goodford, P. J., J. Med. Chem., 1985; 28, 849.

    26. Hansch, C., Hathaway, B. A., Guo, Z. R., Selassie, C. D., Dietrich, S. W., Blaney, J. M., Langridge, R., Volz, K. W., Kaufman, B. T., J. Med. Chem., 1984; 27, 129.

    27. Richard D. Cramer, , III David E. Patterson, Jeffrey D. Bunce, Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins, J. Am. Chem. Soc.; 1988; 110(18), 5959.

    28. James J.P. Stewart, Optimization of Parameters for Semiempirical Methods I. Method, Journal of Computational Chemistry, 1989; 10(2), 209.

    29. James J.P. Stewart, Optimization of Parameters for Semiempirical Methods II. Method, Journal of Computational Chemistry, 1989; 10(2), 221.

    30. James J.P. Stewart, Reply to “Comments on a Comparison of AM1 with the Recently Developed PM3 Method”, Journal of Computational Chemistry, 1990; 11(4), 543.

    31. James J.P. Stewart, Optimization of Parameters for Semiempirical Methods. I11 Extension of PM3 to Be, Mg, Zn, Ga, Ge, As, Se, Cd, In, Sn, Sb, Te, Hg, T1, Pb, and Bi, Journal of Computational Chemistry, 1991; 12(3), 320.

    32. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, Jr., J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople. J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh, PA, 1998.

    33. Sybyl 7.1; Tripos, Inc.: St. Louis, MO, 2005.

    34. Lindberg, W., Persson, J., Wold, S., Anal. Chem., 1983; 55, 643.

    35. Andrew R. Leach, Molecular Modelling, principles and applications., Prentice Hall, second edition, 2001, 701.

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