Title

針對蛋白質激酶活性中心發展親和性化學標示之研究

Translated Titles

Development of active site-directed affinity/alkylating probes for protein kinases

Authors

藍肇穎

Key Words

蛋白質激酶活性標示 ; 分子對接 ; protein kinase ; probe ; docking

PublicationName

臺灣大學化學研究所學位論文

Volume or Term/Year and Month of Publication

2011年

Academic Degree Category

碩士

Advisor

羅禮強

Content Language

繁體中文

Chinese Abstract

本論文以腺苷(adenosine)為基本架構,結合不同的親電子基團、不同長度的連接橋段建構蛋白質激酶的化學標示分子庫,利用有機合成方法,確實地合成出所設計的分子庫,並配合分子模擬計算進行蛋白質激酶:Lymphocyte protein tyrosine kinase、Focal adhesion kinase、mitogen-activated protein kinase與化學標示分子庫的對接加以驗證分子模擬計算和生化實驗的結果,篩選出具有高專一性的化學標示分子。

English Abstract

Using adenosine moiety as basic structure, we aimed at constructing a library of molecular probes for various protein kinases, including Lymphocyte protein tyrosine kinase,focal adhesion kinase, and mitogen-activated protein kinase. The construction of these probes involved the coupling of adenosine with various electrophilic groups that are linked by variable lengths of linkers. By combining the virtue of computational docking and organic syntheses, we have successfully established a library of molecular probes for the computational studies and bio-assay screening aiming at finding the highly specific probes.

Topic Category 基礎與應用科學 > 化學
理學院 > 化學研究所
Reference
  1. (3) Patterson, S. D.; Aebersold, R. H. Nat. Genet. 2003, 33, 311-323.
    連結:
  2. (6) Jeffery, D. A.; Bogyo, M. Current Opinion in Biotechnology 2003, 14, 87-95.
    連結:
  3. (7) Jeffery, D. A.; Bogyo, M. Curr. Opin. Biotechnol. 2003, 14, 87-98.
    連結:
  4. (11) Zhang, Z.-Y. Acc. Chem. Res. 2003, 36, 385-392.
    連結:
  5. (13) Colman, R. F. Annu. Rev. Biochem. 1983, 52, 67-91.
    連結:
  6. (15) Speers, A. E.; Cravatt, B. F. Chem. Biol. 2004, 11, 535-546.
    連結:
  7. (18) Verhelst, S. H. L.; Bogyo, M. QSAR & Combinatorial Science 2005, 24, 261-269.
    連結:
  8. (23) Lan, C.-Y.; Su, M.-D. J. Phys. Chem. A 2007, 111, 6232-6240.
    連結:
  9. (24) Hsiao, J.; Lan, C.-Y.; Su, M.-D. J. Phys. Chem. A 2008, 112, 5300-5304.
    連結:
  10. (26) Box, V. G. S. J. Mol. Model. 1997, 3, 124-141.
    連結:
  11. (28) Taylor, R. D.; Jewsbury, P. J.; Essex, J. W. J. Comput. Aided Mol. Des. 2002, 16, 151-166.
    連結:
  12. (29) Allinger, N. L.; Kao, J. J. Am. Chem. Soc. 1977, 99, 975-986.
    連結:
  13. (30) Allinger, N. L.; Yan, L. J. Am. Chem. Soc. 1993, 115, 11918-11925.
    連結:
  14. (31) Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. J. J. Am. Chem. Soc. 1984, 106, 765-784.
    連結:
  15. (37) Liu, F.; Austin, D. J. Tetrahedron Lett. 2001, 42, 3153-3154.
    連結:
  16. (46) Roberts, W. G.; Ung, E.; Whalen, P.; Cooper, B.; Hulford, C.; Autry, C.; Richter, D.; Emerson, E.; Lin, J.; Kath, J.; Coleman, K.; Yao, L.; Martinez-Alsina, L.; Lorenzen, M.; Berliner, M.; Luzzio, M.; Patel, N.; Schmitt, E.; LaGreca, S.; Jani, J.; Wessel, M.; Marr, E.; Griffor, M.; Vajdos, F. Cancer Res. 2008, 68, 1935-1944.
    連結:
  17. (49) Lavogina, D.; Enkvist, E.; Uri, A. ChemMedChem 2010, 5, 23-34.
    連結:
  18. (50) Jahn, W. Chem. Ber. 1965, 98, 1705-1708.
    連結:
  19. (1) Johnson, L. N. Quarterly Reviews of Biophysics 2009, 42, 1-40.
  20. (2) Greenman, C.; Stephens, P.; Smith, R.; Dalgliesh, G. L.; Hunter, C.; Bignell, G.; Davies, H.; Teague, J.; Butler, A.; Stevens, C.; Edkins, S.; O/'Meara, S.; Vastrik, I.; Schmidt, E. E.; Avis, T.; Barthorpe, S.; Bhamra, G.; Buck, G.; Choudhury, B.; Clements, J.; Cole, J.; Dicks, E.; Forbes, S.; Gray, K.; Halliday, K.; Harrison, R.; Hills, K.; Hinton, J.; Jenkinson, A.; Jones, D.; Menzies, A.; Mironenko, T.; Perry, J.; Raine, K.; Richardson, D.; Shepherd, R.; Small, A.; Tofts, C.; Varian, J.; Webb, T.; West, S.; Widaa, S.; Yates, A.; Cahill, D. P.; Louis, D. N.; Goldstraw, P.; Nicholson, A. G.; Brasseur, F.; Looijenga, L.; Weber, B. L.; Chiew, Y.-E.; deFazio, A.; Greaves, M. F.; Green, A. R.; Campbell, P.; Birney, E.; Easton, D. F.; Chenevix-Trench, G.; Tan, M.-H.; Khoo, S. K.; Teh, B. T.; Yuen, S. T.; Leung, S. Y.; Wooster, R.; Futreal, P. A.; Stratton, M. R. Nature 2007, 446, 153-158.
  21. (4) O'Farrel, P. H. J. Biol. Chem. 1975, 250, 4007-4021.
  22. (5) Lo, L.-C.; Pang, T.-L.; Kuo, C.-H.; Chiang, Y.-L.; Wang, H.-Y.; Lin, J.-J. Journal of Proteome Research 2002, 1, 35-40.
  23. (8) Greenbaum, D.; Medzihradszky, K. F.; Burlingame, A.; Boyo, M. Chem. Biol. 2000, 7, 27-38.
  24. (9) Martins, L. M.; Kottle, T.; Mesner, P. W.; Basi, G. S.; Sinha, S.; Frigon, N.; Tatar, E. J.; Tung, J. S.; Bryant, K.; Takahashi, A.; Svingen, P. A.; Madden, B. J.; McCormick, D. J.; Earnshaw, W. C.; Kaufmann, S. H. J. Biol. Chem. 1997, 272, 7421-7430.
  25. (10) Lin, Y.; Partricelli, M. P.; Cravatt, B. F. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 14694-14699.
  26. (12) Chan, E. W.; Chattopadhaya, S.; Panicker, R. C.; Huang, X.; Yao, S. Q. J. Am. Chem. Soc. 2004, 126, 14435-14446.
  27. (14) Schmidinger, H.; Hermetter, A.; Briner-Gruenberger, R. Amino Acids 2006, 30, 333-350.
  28. (16) Cravatt, B. F.; Wright, A. T.; Kozarich, J. W. Annual Review of Biochemistry 2008, 77, 383-414.
  29. (17) Payne, L. S.; Brown, P. M.; Middleditch, M.; Baker, E.; Cooper, G. J.; Loomes, K. M. Biochem J 2008, 416, 281-288.
  30. (19) Winssinger, N.; Ficarro, S.; Schultz, P. G.; Harris, J. L. Proceedings of the National Academy of Sciences 2002, 99, 11139-11144.
  31. (20) Pearson, R. G. Journal of Chemical Education 1968, 45, 581-null.
  32. (21) Faegri, J. A.; Jr, K.; Korsell, K. J. Comput. Chem. 1982, 3, 385-399.
  33. (22) Schrödinger, E. Annalen der Physik 1926, 385, 437-490.
  34. (25) Born, M.; Oppenheimer, R. Annalen der Physik. 1927, 389, 457-484.
  35. (27) Lennard-Jones, J. E. Proc. R. Soc. Lond. A 1924, 106, 463-477.
  36. (32) Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. 1983, 4, 187-217.
  37. (33) MacKerell, A. D.; Wi6rkiewicz-Kuczera, J.; Karplus, M. J. Am. Chem, Soc. 1995, 117, 11946-11975.
  38. (34) Anderson, H. L. Los Alamos Science 1986, 14, 96-108.
  39. (35) Kirkpatrick, S.; Gelatt, C. D.; Vecchi, M. P. Science 1983, 220, 671-680.
  40. (36) Poppea, L.; Hull, W. E.; Retey, J. Helvetica Chimica Acta 1993, 76, 2367-2383.
  41. (38) Ciuffreda, P.; Loseto, A.; Santaniello, E. Tetrahedron 2002, 58, 5767-5771.
  42. (39) MacCoss, M.; Ryu, E. K.; White, R. S.; Last, R. L. J. Org. Chem. 1980, 45, 788-794.
  43. (40) Reeve, A. M.; Townsend, C. A. Tetrahedron 1998, 54, 15959-15974.
  44. (41) Sato, S.; Tetsuhashi, M.; Sekine, K.; Miyachi, H.; Naito, M.; Hashimotoa, Y.; Aoyamaa, H. Bioorg. Med. Chem. 2008, 16, 4685-4698.
  45. (42) Izatt, R. M.; Hansen, L. D.; Rytting, J. H.; Christensen, J. J. J. Am. Chem. Soc. 1965, 87, 2760-2761.
  46. (43) Jin, S.; Miduturu, C. V.; McKinney, D. C.; Silverman, S. K. J. Org. Chem. 2005, 70, 4284-4299.
  47. (44) Wittmann, V.; Takayama, S.; Gong, K. W.; Weitz-Schmidt, G.; Wong, C.-H. J. Org. Chem. 1998, 63, 5137-5143.
  48. (45) Yamaguchi, H.; Hendrickson, W. A. Nature 1996, 384, 484-489.
  49. (47) Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Nat. Sturct. Biol. 2002, 9, 268-272.
  50. (48) Zhang, J.; Zheng, Q.; Zhang, H. J. Phys. Chem. B 2010, 114, 7383-7390.