Author: |
許正昌 |
---|---|
Thesis Title: |
運用GOLD程式進行具吲哚環的抗微管蛋白化合物之對位計算研究 |
Advisor: | 孫英傑 |
Degree: |
碩士 Master |
Department: |
化學系 Department of Chemistry |
Thesis Publication Year: | 2008 |
Academic Year: | 96 |
Language: | 中文 |
Number of pages: | 76 |
Keywords (in Chinese): | 微管蛋白 癌症 對位研究 |
Thesis Type: | Academic thesis/ dissertation |
Reference times: | Clicks: 90 Downloads: 0 |
Share: |
School Collection Retrieve National Library Collection Retrieve Error Report |
在尋找更好的抗微管蛋白聚合的抑制劑的努力中,最近的實驗測量71個化合物的抗胃癌細胞株的IC50值,這一系列的化合物主要是以TMP、吲哚環(indole ring)和C=O當做橋接鍵為組合片段,在吲哚環上做不同官能基的取代(見下圖)。在本研究中,我們利用GOLD軟體去計算這一系列的化合物與微管蛋白結合的構型與能量,計算結果發現大多數化合物的構型跟微管蛋白結晶結構中的鬼臼毒素(Podophyllotoxin)很類似,從評分函數中可發現決定這類結合模式的主要穩定作用力為凡得瓦作用力,我依此結合模式去設計新的衍生物。在R1~R6測試接不同官能基可發現,(1) R1、R2、R4只適合去接一個重原子為限的官能基,(2) R3可接Et這種非極性官能基,R6可以接類似TMP的官能基。除此之外,從這些計算結果中發現兩個重要的氫鍵作用力,一個是吲哚環上的N-H會跟THR173:O產生氫鍵,另一個是在R6末端接類似TMP的官能基,TMP上中間OMe的氧會跟LYS684產生強烈的氫鍵作用力,這兩個氫鍵作用力對於穩定POD-like構型有一定的貢獻,希望這些發現對於藥物設計能有所幫助。
1. Klebe, G., Virtual ligand screening: strategies, perspectives and limitations. Drug Discovery Today 2006, 11, (13-14), 580-594.
2. Vadivelan, S.; Sinha, B. N.; Irudayam, S. J.; Jagarlapudi, S. A. R. P., Virtual Screening Studies to Design Potent CDK2-Cyclin A Inhibitors. J. Chem. Inf. Model. 2007, 47, (4), 1526-1535.
3. Verdonk, M. L.; Berdini, V.; Hartshorn, M. J.; Mooij, W. T. M.; Murray, C. W.; Taylor, R. D.; Watson, P., Virtual Screening Using Protein-Ligand Docking: Avoiding Artificial Enrichment. J. Chem. Inf. Comput. Sci. 2004, 44, (3), 793-806.
4. Senqupta, S.; Thomas, A. A., Drug target interaction of tubulin-binding drugs in cancer therapy. Expert Rev. Anticancer Ther. 2006, 6, 1433-1447.
5. Nogales, E.; Wang, H.-W., Structural mechanisms underlying nucleotide-dependent self-assembly of tubulin and its relatives. Current Opinion in Structural Biology 2006, 16, (2), 221-229.
6. Kim, D. Y.; Kim, K. H.; Kim, N. D.; Lee, K. Y.; Han, C. K.; Yoon, J. H.; Moon, S. K.; Lee, S. S.; Seong, B. L., Design and Biological Evaluation of Novel Tubulin Inhibitors as Antimitotic Agents Using a Pharmacophore Binding Model with Tubulin. J. Med. Chem. 2006, 49, (19), 5664-5670.
7. Jordan, M. A.; Wilson, L., Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004, 4, (4), 253-265.
8. Bhat, K. M. R.; Setaluri, V., Microtubule-Associated Proteins as Targets in Cancer Chemotherapy. Clin Cancer Res 2007, 13, (10), 2849-2854.
9. Sardar, P. S.; Maity, S. S.; Das, L.; Ghosh, S., Luminescence Studies of Perturbation of Tryptophan Residues of Tubulin in the Complexes of Tubulin with Colchicine and Colchicine Analogues. Biochemistry 2007, 46, (50), 14544-14556.
10. Hande, K. R., Etoposide: four decades of development of a topoisomerase II inhibitor. European Journal of Cancer 1998, 34, (10), 1514-1521.
11. Makino, S.; Kuntz, I. D., Automated flexible ligand docking method and its application for database search. Journal of Computational Chemistry 1997, 18, (14), 1812-1825.
12. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J., Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry 1998, 19, (14), 1639-1662.
13. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R., Development and validation of a genetic algorithm for flexible docking. Journal of Molecular Biology 1997, 267, (3), 727-748.
14. Ruben Abagyan; Totrov, M.; Kuznetsov, D., ICM - A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation. Journal of Computational Chemistry 1994, 15, (5), 488-506.
15. Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G., A Fast Flexible Docking Method using an Incremental Construction Algorithm. Journal of Molecular Biology 1996, 261, (3), 470-489.
16. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S., Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47, (7), 1739-1749.
17. Jain, A. N., Surflex: Fully Automatic Flexible Molecular Docking Using a Molecular Similarity-Based Search Engine. J. Med. Chem. 2003, 46, (4), 499-511.
18. McMartin, C.; Bohacek, R. S., QXP: Powerful, rapid computer algorithms for structure-based drug design. Journal of Computer-Aided Molecular Design 1997, 11, 333-344.
19. Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Preti, D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; DiCristina, A.; Balzarini, J.; Hadfield, J. A.; Brancale, A.; Hamel, E., Synthesis and Biological Evaluation of 2- and 3-Aminobenzo[b]thiophene Derivatives as Antimitotic Agents and Inhibitors of Tubulin Polymerization. J. Med. Chem. 2007, 50, (9), 2273-2277.
20. Romagnoli, R.; Baraldi, P. G.; Remusat, V.; Carrion, M. D.; Cara, C. L.; Preti, D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Balzarini, J.; Jordan, M. A.; Hamel, E., Synthesis and Biological Evaluation of 2-(3',4',5'-Trimethoxybenzoyl)-3-Amino 5-Aryl Thiophenes as a New Class of Tubulin Inhibitors. J. Med. Chem. 2006, 49, (21), 6425-6428.
21. LaRegina, G.; Edler, M. C.; Brancale, A.; Kandil, S.; Coluccia, A.; Piscitelli, F.; Hamel, E.; DeMartino, G.; Matesanz, R.; Diaz, J. F.; Scovassi, A. I.; Prosperi, E.; Lavecchia, A.; Novellino, E.; Artico, M.; Silvestri, R., Arylthioindole Inhibitors of Tubulin Polymerization. 3. Biological Evaluation, Structure-Activity Relationships and Molecular Modeling Studies. J. Med. Chem. 2007, 50, (12), 2865-2874.
22. Bellina, F.; Cauteruccio, S.; Monti, S.; Rossi, R., Novel Imidazole-Based Combretastatin A-4 Analogues: Evaluation of Their in vitro Antitumor Activity and Molecular Modeling Study of Their Binding to the Colchicine Site of Tubulin. ChemInform 2007, 38, (13).
23. Liou, J. P.; Chang, Y. L.; Kuo, F. M.; Chang, C. W.; Tseng, H. Y.; Wang, C. C.; Yang, Y. N.; Chang, J. Y.; Lee, S. J.; Hsieh, H. P., Concise Synthesis and Structure-Activity Relationships of Combretastatin A-4 Analogues, 1-Aroylindoles and 3-Aroylindoles, as Novel Classes of Potent Antitubulin Agents. J. Med. Chem. 2004, 47, (17), 4247-4257.
24. Ravelli, R. B. G.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M., Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 2004, 428, (6979), 198-202.
25. Lovell, S. C.; Word, J. M.; Richardson, J. S.; Richardson, D. C., The penultimate rotamer library. Proteins: Structure, Function, and Genetics 2000, 40, (3), 389-408.
26. Schlessinger, A.; Rost, B., Protein flexibility and rigidity predicted from sequence. Proteins: Structure, Function, and Bioinformatics 2005, 61, (1), 115-126.
27. Verdonk, M. L.; Chessari, G.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Nissink, J. W. M.; Taylor, R. D.; Taylor, R., Modeling Water Molecules in Protein-Ligand Docking Using GOLD. J. Med. Chem. 2005, 48, (20), 6504-6515.
28. Cole, J. C.; Murray, C. W.; Nissink, J. W. M.; Taylor, R. D.; Taylor, R., Comparing protein-ligand docking programs is difficult. Proteins: Structure, Function, and Bioinformatics 2005, 60, (3), 325-332.
29. Eldridge, M. D.; Murray, C. W.; Auton, T. R.; Paolini, G. V.; Mee, R. P., Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. Journal of Computer-Aided Molecular Design 1997, 11, (5), 425-445.
30. Baxter, C. A.; Murray, C. W.; Clark, D. E.; Westhead, D. R.; Eldridge, M. D., Flexible docking using tabu search and an empirical estimate of binding affinity. Proteins: Structure, Function, and Genetics 1998, 33, (3), 367-382.
31. Mooij, W. T. M.; Verdonk, M. L., General and targeted statistical potentials for protein-ligand interactions. Proteins: Structure, Function, and Bioinformatics 2005, 61, (2), 272-287.
32. Jones, G.; Willett, P.; Glen, R. C., Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. Journal of Molecular Biology 1995, 245, (1), 43-53.
33. Gupta, S.; Das, L.; Datta, A. B.; Poddar, A.; Janik, M. E.; Bhattacharyya, B., Oxalone and Lactone Moieties of Podophyllotoxin Exhibit Properties of Both the B and C Rings of Colchicine in Its Binding with Tubulin. Biochemistry 2006, 45, (20), 6467-6475.
34. Nguyen, T. L.; McGrath, C.; Hermone, A. R.; Burnett, J. C.; Zaharevitz, D. W.; Day, B. W.; Wipf, P.; Hamel, E.; Gussio, R., A Common Pharmacophore for a Diverse Set of Colchicine Site Inhibitors Using a Structure-Based Approach. J. Med. Chem. 2005, 48, (19), 6107-6116.