臺灣博碩士論文加值系統

隨著計算機科學的快速進展，結合電腦圖形、藥學和結構生物學的工具來加速藥物的開發已漸漸成為藥物設計中的重要課題，而其中定量結構-活性關係（Quantitative structure-activity relationship）模型的建立與分子接合模擬（Molecular docking）是許多藥廠非常感興趣的領域。本論文即針對338個有活性的愛滋病病毒蛋白水解酶抑制劑（HIV protease inhibitor）進行了一系列的分子凸狀殼（Convex hull）特性計算與分子接合(docking)模擬，目的在找出分子凸狀殼、接合能量與活性之間的關係以作為往後改良分子描述器之參考。透過傳統迴歸分析與羅吉斯迴歸(Logistic regression)的方法，我們發現分子凸狀殼雖無法直接建立與活性的線性關係，但其與活性間卻存有一個群集（Clustering）的關係。此外我們也發現若對活性與分子模擬接合之能量進行相關分析，其中並無顯著的相關性。這顯示了若欲建立分子接合能量與活性間的相關模型，我們勢必要建立一個更精確的評分函數（Scoring function）與較為完整的結構搜尋方式。

With the rapid progression in computational science, methods that integrate computer graphics, pharmacology and structural biology to accelerate drug development have become an important subject in drug design. Among these methods, building of quantitative structure-activity relationship（QSAR）model and molecular docking simulation are areas that drug companies especially interested in. In this thesis, the relation- ship between molecular convex hull property, docking energy and activity has been studied by using 338 HIV protease inhibitors as material. With the use of conventional regression and Logistic Regression, we have found that although the linear regression model can not be built, it does exist a clustering relationship between our convex hull descriptor and activity. In addition, there is not an obvious relationship between docking energy and activity. In order to build a model between activity and docking energy, a more precise scoring function and structure -searching algorithm should be developed.

中文摘要 -------------------------------------------------------------------------- 1
英文摘要 -------------------------------------------------------------------------- 2
第一章 序論 -------------------------------------------------------------- 3
第一節 研究動機 -------------------------------------------------------- 3
第二節 研究目的 -------------------------------------------------------- 4
第二章 文獻探討 -------------------------------------------------------- 5
第一節 HIV-1與HIV-1 PR之特性描述 -------------------------------- 5
第二節 凸狀殼理論 -------------------------------------------------------- 10
第三節 分子接合 -------------------------------------------------------- 11
第三章 材料與方法 -------------------------------------------------- 17
第一節 PI分子結構之建立 -------------------------------------------- 17
第二節 凸狀殼描述器計算 -------------------------------------------- 18
第三節 分子接合模擬流程與參數設定 -------------------------------- 19
第四章 結果 -------------------------------------------------------------- 21
第一節 分子凸狀殼性質與活性之線性關係模型建立 -------------- 21
第二節 分子凸狀殼性質與活性之羅吉斯迴歸模型建立 ----------- 23
第三節 接合能量與活性之相關性分析 -------------------------------- 24
第五章 討論 -------------------------------------------------------------- 26
第一節 分子凸狀殼描述器之模型討論 -------------------------------- 26
第二節 分子接合模擬結果之討論 -------------------------------------- 27
第六章 參考資料 -------------------------------------------------------- 56
附錄 338個HIV PI之分子結構與活性表 -------------- 62

1. Petsko, G. A . For medicinal purposes. Nature. 1996, 384, 7—9.
2. Mark von Itztein; Wen-Yang Wu; Gaik B. Kok; Michael S. Pegg; Jeffrey C. Dyason; Betty Jin, Tho Van Phan; Mark L. Smythe; Hume F. White; Stuart W. Oliver; Peter M Colman; Joseph N. Varghese;D. Michael Ryan; Jacqueline M. Woods; Richard C. Bethell; Vanessa J. Hotham; Janet M. Cameron and Charles R. Penn. Rational design of potent sialidase-based inhibitors of influenza replication. Nature. 1993, 363, 418-423.
3. Brian K. Shoichet; Robert M. Stroud; Daniel V. Santi; Irwin D. Kuntz and Kathy M. Perry. Structure-Based Discovery of Inhibitors of Thymidylate Synthase. Science. 1993, 259, 1445-1450.
4. Christine S. Ring; Eugene Sun; James H. McKerrow; Garson K. Lee; Philip J. Rosenthal; Irwin D. Kuntz and Fred E. Cohen. Structure- based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci. USA. 1993, 90, 3583-3587.
5. I-Jen Chen; Nouri Neamati; Marc C. Nicklaus; Ann Orr; Lynne Anderson; Joseph J. Barchi Jr.; James A. Kelley; Yves Pommier and Alexander D. MacKerell Jr. Identification of HIV-1 Integrase Inhibitors via Three- Dimensional Database Searching Using ASV and HIV-1 Integrases as Targets. Bioorg Med Chem. 2000, 8, 2385-2398.
6. Jun Xu and James Stevenson. Drug-like Index: A New Approach To Measure Drug-like Compounds and Their Diversity. J Chem Inf Comput Sci. 2000, 40, 1177-1187.
7. Ajay, W. Patrick Walters and Mark A. Murcko. Can We Learn To Distinguish between “Drug-like” and “Nondrug-like” Molecules? J Med Chem. 1998, 41, 3314-3324.
8. Brian K. Schoichet; Dale L. Bodian and Irwin D. Kuntz. Molecular Docking Using Shape Descriptor. J Comput Chem. 1992, 13, 380-397.
9. World Health Organization, Jonit of United Nations Programme on HIV/AIDS. http://www.who.int/emc-hiv/
10. 行政院衛生署疾病管制局AIDS統計資料. http://203.65.72.83/ch/das/ShowPublication.ASP?RecNo=931
11. Vanden Haesevelde M.; Decourt J. L.; De Leys R. J.; Vanderborght B.; Van der Groen G.; van Heuverswijn H. and Saman, E. Genomic cloning and complete sequence analysis of ahighly divergent African human immounodeficiency virus isolate. J Virol. 1994, 68, 1586-1596.
12. Langtry, H.D. and Campoli-Richards, D. M. Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs. 1989, 37, 408-50.
13. Faulds D. and Brogden R.N. Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs. 1992, 44, 94-116.
14. Whittington, R. and Brogden,R.N.Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). Drugs. 1992, 44, 656-83.
15. Navia, M. A.; P. M. Fitzgerald; B. M. McKeever; C. T. Leu; J. C. Heimbach; W. K. Herber; I. S. Sigal; P. L. Darke and J. P. Springer. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature. 1989, 337, 615-20.
16. DesJarlais RL; Seibel GL; Kuntz ID; Furth PS; Alvarez JC; Ortiz de Montellano PR; DeCamp DL; Babe LM; Craik CS. Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease. Proc Natl Acad Sci. USA. 1990, 87, 6644-6648.
17. Vacca JP; Guare JP; deSolms SJ; Sanders WM; Giuliani EA; Young SD; Darke PL; Zugay J; Sigal IS and Schleif WA. L-687,908, a potent hydroxyethylene-containing HIV protease inhibitor. J Med Chem. 1991, 34, 1225-1228.
18. Ashorn P; McQuade TJ; Thaisrivongs S; Tomasselli AG; Tarpley WG and Moss B. An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection. Proc Natl Acad Sci. USA. 1990, 87, 7472-7476.
19. Humber DC; Cammack N; Coates JA; Cobley KN; Orr DC; Storer R; Weingarten GG and Weir MP. Penicillin derived C2-symmetric dimers as novel inhibitors of HIV-1 proteinase. J Med Chem. 1992, 35, 3080-3081.
20. Thaisrivongs, S.; Yang, C. P.; Strohbach, J. W.; Turner, S. R.; Romero, D. L. and Skaletzky, L.Patent No. 9411361.
21. Bashford, C. B.; Dobkin, P. D. and Huhdanpaa, H. The Quickhull Algorithm for Convex Hulls. ACM Transaction on Mathematical Software. 1996, 22, 469-483.
22. Leung, Y.; Zhang, J. S. and Xu, Z. B. Neural Networks for Convex Hull Comptation. IEEE Transactions on Neural Networks. 1997, 8, 601-611.
23. Thy-Hou Lin; Yih-Shiang Yu and Hong-Jih Chen. Classification of Some Active Compounds and Their Inactive Analogues Using Two Three-Dimensional Molecular Descriptors Derived from Computation of Three-Dimensional Convex Hulls for Structures Theoretically Generated for Them. J Chem Inf Comput. Sci. 2000, 40, 1210-1221.
24. Thy-Hou Lin; Jia-Jiunn Lin; Yung-Feng Huang and Jin-Hwang Liu. Clustering Peptide Structures through Identification of Commonly Exposed Groups. J Chem Inf Comput Sci. 1999, 39, 622-629.
25. Thy-Hou Lin; Wen-Jiun Peng and Yuh-Jy Lu. Identication of Convexity as a Common Structure Feature for Structures Generated for Two Short Peptides. Computers Chem. 1998, 22, 309-320.
26. Gareth Thomas. Medicinal Chemistry: An introduction. John Wiley & Sons, Ltd.
27. Inbal Halperin; Buyong Ma; HaimWolfson and Ruth Nussinov. Principle of Docking: An Overview of Search Algorithm and a Guide to Scoring Functions. PROTEINS. 2002, 47, 409—443.
28. Janin J. Elusive affinities. PROTEINS. 1995, 21, 30-39.
29. Aqvist J; Medina C and Samuelsson JE. A new method for predicting binding affinity in computer-aided drug design. Protein Eng. 1994, 7, 385-91
30. Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W. & Kollman, P. A. A 2nd generation force-field for the simulation of pro-teins, nucleic-acids, and organic-molecules. J Am Chem Soc. 1995, 117, 5179—5197.
31. MacKerell, A. D.; Bashford, D.; Bellott, M.; Dunbrack, R. L.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E.; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D. and Karplus, M. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem. 1998, 102, 3586—3616.
32. Gilson, M. K.; Sharp, K. A. and Honig, B. H. Calculating the electrostatic potential of molecules in solution: method and error assessment. J Comput Chem. 1988, 9, 327—335.
33. McMartin, C. and Bohacek, R. S. QXP: Powerful, rapid computer algorithms for structure-based drug design. J Comput Aided Mol Des. 1997, 11, 333—344.
34. Nikhil Nair and Jonathan M. Goodman. Genetic Algorithms in Conformational Analysis. J Chem Inf Comput Sci. 1998, 38, 317-320.
35. Rarey, M.; Wefing, S. and Lengauer, T. Placement of medium-sized molecular fragments into active sites of proteins. J Comput Aided Mol Des. 1996, 10, 41—54.
36. Todd J. A. Ewing; Shingo Makino; A. Geoffrey Skillman and Irwin D. Kuntz. DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des. 2001, 15, 411—428.
37. DOCK4.0 manual. http://www.cmpharm.ucsf.edu/kuntz/dock.html
38. G. Jones; P. Willett; R. C. Glen; A.R. Leach and R. Taylor. Development and Validation of a Genetic Algorithm for Flexible Docking. J Mol Biol. 1997, 267, 727-748.
39. G. Jones; P. Willett and R. C. Glen. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation. J Mol Biol. 1995, 245, 43-53.
40. B. Kramer; M. Rarey and T. Lengauer. Evaluation of the FlexX incremental construction algorithm for protein-ligand docking. PROTEINS. 1999, 37, 228-241.
41. D. Hoffmann; B. Kramer; T. Washio; T.Steinmetzer; M. Rarey and T. Lengauer. Two-Stage Method for Protein-Ligand Docking.J Med Chem. 1999, 42, 4422-4433.
42. Morris, G. M.; Goodsell, D. S.; Halliday, R.S.; Huey, R.; Hart, W. E.; Belew, R. K. and Olson, A. J. Automated Docking Using a Lamarckian Genetic Algorithm and and Empirical Binding Free Energy Function. J Comput Chem. 1988, 19, 1639-1662.
43. Kuntz, I.D.; Blaney, J.M.; Oatley, S.J.; Langridge, R. and Ferrin, T.E. A geometric approach to macromolecule-ligand interactions. J Mol Biol. 1982, 161, 269-288.
44. M. L. Connolly. Analytical molecular surface calculation. Journal of applied crystallography. 1983, 16, 548-558.
45. Hulte´n, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon, B.; Danielson, U. H.; Karle´n, A.; Kvarnstro¨m, I.; Samuelsson, B. and Hallberg, A.. Cyclic HIV-1 Protease Inhibitors Derived from Mannitol: Synthesis, Inhibitory Potencies, and Computational Predictions ofBinding Affinities. J Med Chem. 1997, 40, 885-897.
46. Alterman, M.; Bjo’rsne, M.; Mu’hlman, A.; Classon, B.; Kvarnstro’m, I.; Danielson, H.; Markgren, P. O.; Nillroth, U.; Unge, T.; Hallberg, A. and Samuelsson, B. Design and Synthesis of New Potent C2-Symmetric HIV-1 Protease Inhibitors. Use of L-Mannaric Acidas a Peptidomimetic Scaffold. J Med Chem. 1998, 41, 3782-3792.
47. Nugiel, D. A.; Jacobs, K.; Cornelius, L.; Chang, C.; Jadhav, P. K.; Holler, E. R.; Klabe, R. M.; Bacheler, L. T.;Cordova, B.; Garber, S.; Reid, C.; Logue, K. A.; Gorey-Feret, L.J.; Lam, G. N.; Erickson- Viitanen, S. and Seitz, S. P. Improved P1/P1’Substituents for Cyclic Urea Based HIV-1 Protease Inhibitors: Synthesis, Structure-Activity Relationship, and X-ray Crystal Structure Analysis. J Med Chem. 1997, 40, 1465-1474.
48. Kroemer, R. T.; Ettmayer, P. and Hecht, P. 3D-Quantitative Structure-Activity Relationship of Human Immunodeficiency Virus Type-1 Proteinase Inhibitors: Comparative Molecular Field Analysis of 2-Heterosubstituted Statine Derivatives-Implications for the Design of Novel Inhibitors. J Med Chem. 1995, 38, 4917-4928.
49. Scholz, D.; Billich, A.; Charpiot, B.; Ettmayer, P.; Lehr, P.; Rosenwirth, B.; Schreiner, E. and Gstach, H. Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5- phenyl- pentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity. J Med Chem. 1994, 37, 3079-3089.
50. Mathias Alterman; Hans O. Andersson; Neeraj Garg; Go’ran Ahlsen; Seved Lo’vgren; Bjo’rn Classon; U. Helena Danielson; Ingmar Kvarnstro’mr Lotta Vrang; Torsten Unge; Bertil Samuelsson and Anders Hallberg. Design and Fast Synthesis of C-Terminal Duplicated Potent C2-Symmetric P1/P1-Modified HIV-1 Protease Inhibitors. J Med Chem. 1999, 42, 3835-3844.
51. Asim Kumar Debnath. Three-Dimensional Quantitative Structure- Activity Relationship Study on Cyclic Urea Derivatives as HIV-1 Protease Inhibitors: Application of Comparative Molecular Field Analysis. J Med Chem. 1999, 42, 249-259.
52. Prabhakar K. Jadhav; Paul Ala. Francis J. Woerner; Chong-Hwan Chang; Sena S. Garber; Elizabeth D. Anton and Lee T. Bacheler. Cyclic Urea Amides: HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV. J Med Chem. 1997, 40, 181-191.
53. Brookhaven Protein Data Bank. http://www.rcsb.org/pdb/
54. SYBYL Molecular Modeling System (Version 6.7) from Tripos Associates Inc.
55. MDL Information Systems Inc.
56. QCPE Program Number 429, http://www.qcpe.indiana.edu
57. RasMol Home Page. http://www.umass.edu/microbio/rasmol/
58. Eiichi AKACHO; Garret MORRIS; David GOODSELL; David WONG and Arthur OLSON. A Study on Docking Mode of HIV Protease and Their Inhibitors. J. Chem. Software. 2001, 7, 103-114