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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57045完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾宇鳳(Y. Jane Tseng) | |
| dc.contributor.author | Kuo-Hsiang Hsu | en |
| dc.contributor.author | 徐國翔 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:33:36Z | - |
| dc.date.available | 2019-09-05 | |
| dc.date.copyright | 2014-09-05 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-04 | |
| dc.identifier.citation | 1. Ames, B. N.; Lee, F. D.; Durston, W. E., An Improved Bacterial Test System for the Detection and Classification of Mutagens and Carcinogens. Proceedings of the National Academy of Sciences 1973, 70 (3), 782-786.
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T.; Muller, L., Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities. Regulatory Toxicology and Pharmacology 2013, 67 (1), 39-52. 21. Serafimova, R.; Todorov, M.; Pavlov, T.; Kotov, S.; Jacob, E.; Aptula, A.; Mekenyan, O., Identification of the Structural Requirements for Mutagencitiy, by Incorporating Molecular Flexibility and Metabolic Activation of Chemicals. II. General Ames Mutagenicity Model. Chemical Research in Toxicology 2007, 20 (4), 662-676. 22. Kho, R.; Hodges, J. A.; Hansen, M. R.; Villar, H. O., Ring Systems in Mutagenicity Databases. Journal of Medicinal Chemistry 2005, 48 (21), 6671-6678. 23. Chanin Nantasenamat, C. I.-N.-A., Thanakorn Naenna, and Virapong Prachayasittikul., A practical overview of quantitative structure-activity relationship. Excli Journal (July 06, 2014). 24. Stefan Wetzel, K. K., Steffen Renner, Daniel Rauh, Tudor I Oprea, Petra Mutzel & Herbert Waldmann, Interactive exploration of chemical space with Scaffold Hunter. Nat Chem Biol 2009. 25. Bemis, G. W.; Murcko, M. A., The Properties of Known Drugs. 1. Molecular Frameworks. Journal of Medicinal Chemistry 1996, 39 (15), 2887-2893. 26. (a) Contrera, J. F., Validation of Toxtree and SciQSAR in silico predictive software using a publicly available benchmark mutagenicity database and their applicability for the qualification of impurities in pharmaceuticals. Regulatory Toxicology and Pharmacology 2013, 67 (2), 285-293; (b) Webb, S. J.; Hanser, T.; Howlin, B.; Krause, P.; Vessey, J. D., Feature combination networks for the interpretation of statistical machine learning models: application to Ames mutagenicity. J. Cheminformatics 2014, 6 (1), 8. 27. System, C. C. R. I. on the NCRI Informatics Initiative Homepage July 17, 2009. 28. Helma, C.; Cramer, T.; Kramer, S.; De Raedt, L., Data Mining and Machine Learning Techniques for the Identification of Mutagenicity Inducing Substructures and Structure Activity Relationships of Noncongeneric Compounds. Journal of Chemical Information and Computer Sciences 2004, 44 (4), 1402-1411. 29. Kazius, J.; McGuire, R.; Bursi, R., Derivation and Validation of Toxicophores for Mutagenicity Prediction. Journal of Medicinal Chemistry 2004, 48 (1), 312-320. 30. Feng, J.; Lurati, L.; Ouyang, H.; Robinson, T.; Wang, Y.; Yuan, S.; Young, S. S., Predictive Toxicology: Benchmarking Molecular Descriptors and Statistical Methods. Journal of Chemical Information and Computer Sciences 2003, 43 (5), 1463-1470. 31. Judson, P. N.; Cooke, P. A.; Doerrer, N. G.; Greene, N.; Hanzlik, R. P.; Hardy, C.; Hartmann, A.; Hinchliffe, D.; Holder, J.; Muller, L.; Steger-Hartmann, T.; Rothfuss, A.; Smith, M.; Thomas, K.; Vessey, J. D.; Zeiger, E., Towards the creation of an international toxicology information centre. Toxicology 2005, 213 (1–2), 117-128. 32. Toxicity, G., Reproductive and Developmental Toxicity, and Carcinogenicity Database. http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm092217.htm (accessed July 17, 2009). 33. Wetzel, S.; Klein, K.; Renner, S.; Rauh, D.; Oprea, T. I.; Mutzel, P.; Waldmann, H., Interactive exploration of chemical space with Scaffold Hunter. Nat Chem Biol 2009, 5 (8), 581-583. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57045 | - |
| dc.description.abstract | 由於艾美氏致突變性試驗需要耗時兩個禮拜並且測量每個化合物在一個濃度之下針對五個沙門氏菌品系需要3110美金，因此電腦模擬預測模型便被Committee for Medicinal Products for Human Use (CHMP) 推薦在藥物發展過程中於臨床前階段使用作為初步篩選的工具。目前用於艾美氏致突變性的工具主要有兩種: 結構性警示以及定量構效關係。結構性警示著重於功能性基團而定量構效關係則著重於系列類似物的支鏈。這兩種方法並不提供關於致突變性的化合物骨架結構資訊，因此當化合物的致癌性質是由於它的骨架結構而不是他的子結構時，這兩種方法的幫助就不大。
本篇論文中我們從大量的化學結構中分析其骨架結構以及它們的致突變性質，對資料進行階層化的整理並建構出骨架結構樹，針對化學結構中骨架與致突變性的關係做進一步分析。 艾美氏致突變性試驗的結果常做為致癌性的參考指標，因為致突變性質與致癌性有相當緊密的關聯性。在本論文中藉由過去艾美氏致突變性試驗的結果，利用結構獵人進行化合物骨架結構的分析建構出骨架結構樹，並透過骨架結構樹之間的親子關系列出主要含有致突變性質的化合物骨架結構清單。對於部分含有致突變性質的化合物骨架結構也利用骨架結構樹的同輩關系列出了一些結構上的修改建議。化合物骨架結構是藉由結構獵人分析而得來的。結構獵人不只計算了化合物的化學骨架也建立了一個描繪出結構骨架之間關係的骨架樹。這樣的關係可以用來修改有潛在致突變性可能的骨架結構變成沒有突變可能的骨架結構。詳細的致突變性骨架結構以及無致突變性骨架結構的列表也可藉由這樣的的骨架樹分析來建立。這樣的列表對於藥物發展是很有幫助的，特別是在臨床前的領導結構的修改以及安全性篩選階段。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:33:36Z (GMT). No. of bitstreams: 1 ntu-103-R00945019-1.pdf: 1863684 bytes, checksum: 5840860c87734a6b1ee622dcc850dda3 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | ACKNOWLEGEMENTS i
中文摘要 ii ABSTRACT iv TABLE OF CONTENTS vi LIST OF FIGURES ix LIST OF TABLES xi 1 Introduction 1 1.1 Background 1 1.2 Current Structural Alert- and QSAR-Based Models for Ames Prediction 3 1.2.1 DEREK for Windows (DfW) 4 1.2.2 Toxtree 5 1.2.3 MC4PC (MultiCASE) 6 1.2.4 Leadscope Model Applier (LSMA) 7 1.3 Limitations of Current Ames Prediction Models 8 1.4 Core Structure List of Mutagens 10 2 Materials and Methods 11 2.1 Benchmark Data Set: Ames Mutagenicity 11 2.2 Construction of Ames Mutagenicity Scaffold Trees 13 2.2.1 Scaffold Hunter 13 2.3 Analysis of Ames Mutagenicity Scaffold Trees 17 2.3.1 Cutoffs for Selecting Mutagenic and Non- Mutagenic Scaffolds 17 3 Results and Discussion 19 3.1 Cutoff Criteria for Selecting Mutagenic and Non- Mutagenic Scaffolds 20 3.2 Major Mutagenic Scaffolds of the Ames Mutagenicity Scaffold Tree 29 3.2.1 Major Mutagenic Scaffolds of the Acridine Group 30 3.2.2 Major Mutagenic Scaffolds in the Phenanthrene Group 33 3.2.3 Major Mutagenic Scaffolds in the Pyrene Group 36 3.2.4 Major Mutagenic Scaffolds in the Quinoxaline Group 39 3.3 Minor Mutagenic Scaffolds of the Ames Mutagenicity Tree 42 3.3.1 Minor Mutagenic Scaffolds in the Naphthalene Group 43 3.3.2 Minor Mutagenic Scaffolds in the Benzene Group 46 3.3.3 Minor Mutagenic Scaffolds in the Quinoline Group 48 3.4 Reduction of Mutagenicity via Substructure Modification 52 3.4.1 Structural Modification of Benzo[c]acridine and N-Phenylacridin-9-amine 53 3.4.2 Structure Modification of 15,16-Dihydro-cyclopenta[a]-phenanthren-17-one and Chrysene 55 3.4.3 Structure Modification of 1H-Imidazo[4,5-g]quinoxaline and Phenazine 57 3.4.4 Structure Modification of Anthracene and Phenanthrene 59 3.4.5 Structure Modification of Acridine 61 3.5 Comparison with the Structure Alert Approach (Toxtree) 63 4 Limitations 67 5 Conclusion 68 REFERENCES 72 | |
| dc.language.iso | zh-TW | |
| dc.subject | 骨架分析 | zh_TW |
| dc.subject | 艾美氏致突變性試驗 | zh_TW |
| dc.subject | Ames Mutagenicity | en |
| dc.subject | Scaffold Analysis | en |
| dc.title | 艾美氏致突變性試驗的化學結構之骨架分析 | zh_TW |
| dc.title | Scaffold Analysis of Ames Mutagenicity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 劉玉麗(Yu-Li Liu),陳俊良(Chuen-Liang Chen) | |
| dc.subject.keyword | 艾美氏致突變性試驗,骨架分析, | zh_TW |
| dc.subject.keyword | Ames Mutagenicity,Scaffold Analysis, | en |
| dc.relation.page | 75 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-05 | |
| dc.contributor.author-college | 電機資訊學院 | zh_TW |
| dc.contributor.author-dept | 生醫電子與資訊學研究所 | zh_TW |
| 顯示於系所單位： | 生醫電子與資訊學研究所 | |
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