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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 曾宇鳳 | |
dc.contributor.author | Yi-Syuan Huang | en |
dc.contributor.author | 黃薏璇 | zh_TW |
dc.date.accessioned | 2021-06-15T06:01:32Z | - |
dc.date.available | 2015-08-17 | |
dc.date.copyright | 2010-08-17 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-17 | |
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Smalley, Daniel Fong, Yong-Liang Zhu, Adhirai Marimuthu, Hoa Nguyen, Billy Lam, Jennifer Liu, Ivana Cheung, Julie Rice, Yoshihisa Suzuki, Catherine Luu, Calvin Settachatgul, Rafe Shellooe, John Cantwell, Sung-Hou Kim, Joseph Schlessinger, Kam Y. J. Zhang, Brian L. West, Ben Powell, Gaston Habets, Chao Zhang, Prabha N. Ibrahim, Peter Hirth, Dean R. Artis, Meenhard Herlyn, and Gideon Bollag Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. PNAS 2008, 105, 3041-3046. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47473 | - |
dc.description.abstract | Vascular endothelial growth factor receptor 2 and 3 (VEGFR-2/3) are important protein kinases targets for angiogenesis and lymphangiogenesis of cancer treatments. Most “Type I kinase inhibitors” are ATP competitive while “Type II kinase inhibitors” target the inactive form of kinase by interacting with a hydrophobic allosteric site created by the outstretched DFG domain. Designing compounds with good inhibition, selectivity, specificity and solubility is challenging for kinase inhibitors. It would be beneficial to start with a known drug and use its physicochemical properties and binding mode as a template.
In this study, we developed a fragment-based de novo design strategy to design novel type II VEGFR-2/3 inhibitors based on sorafenib (Nexavar®) , a known Type II kinase inhibitor. Three steps were employed in the design of new VEGFR-2/3 inhibitors. First, the inactive VEGFR-2/3 binding pocket, where sorafenib binds, was divided into an allosteric site, linker spacer, and ATP binding site. Second, potential active site fragments were selected from the Scifinder database and used to flood the binding site. Eight docked poses for each fragment were selected from the ensemble, located in the ATP binding and the allosteric site, and each fragment was prioritized based on a group efficiency score and selected via drug-likeness filters. The final step generates a series of new compounds by linking fragments that have an average of three alternative connections per linker. The new compound was prescribed a bound conformation similar to that of the known ligand (preserving key receptor - ligand interactions) and analyzed. To test the performance of our method, we were able to re-generate sorafenib and its analogues and another type II inhibitor – nilotinib (Tasigna®) automatically from a total combination of 1330 fragments for each segment of the binding site; eight docked poses for each fragment and average 3 linker attachment points for each linker. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:01:32Z (GMT). No. of bitstreams: 1 ntu-99-R97945021-1.pdf: 4804169 bytes, checksum: b38c0c929764cd5537d30a959cfeba9e (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | Table of Contents
口試委員會審定書………………………………………………… i 致謝…………………………………………………………………… ii 中文摘要…………………………………………………………… iii Abstract…………………………………………………………… iv List of Figures……………………………………………… vii List of Tables…………………………………………………… viii Chapter 1. Introduction…………………………………………… 1 1.1Introduction…………………………………………………… 1 1.2 Literature reviews of VEGFR and its inhibitors. 5 1.2.1 Kinases physiology and its structures………… 5 1.2.2 VEGFR physiology and its structure…………… 11 1.2.3 Type II inhibitors………………………… 14 Chapter 2. Materials and Methods…………………………… 17 2.1 Main Algorithm………………………………………… 17 2.2 Allocate the Three Functional Boxes…………… 17 2.3 Data Set………………………………………………… 18 2.4 Validation Set………………………………………… 19 2.5 Molecular Docking…………………………………… 23 2.6 Group Efficiency……………………………………… 24 2.7 Generation of New Structures……………………… 24 2.8 Drug-likeness Filtering…………………………… 26 2.9 Molecular Dynamics Simulation…………………… 27 2.10 Structure Interaction Residues Analysis……… 28 2.11 Clustering based on 4D FingerPrints (4DFPs) … 29 Chapter 3. Results and Discussions………………………… 31 3.1 Analysis of Sorafenib Binding Pocket…………… 31 3.2 Re-assembling of Our Template : Validation with Sorafenib and Its Analogues…34 3.3 Docking Binding Energies and GE Scores of Building Blocks…… 36 3.4 Newly Generated Structures………………………… 37 3.5 Analysis of Structural Interaction Residues… 43 3.6 Clustering based on the 4DFP…………………………47 3.7 Application of a Series of Aminoisoquinoline Compounds of Mutant BRAF………49 3.8 Application of ABL and Nilotinib……………… 52 Chapter 4. Conclusions………………………………………………………… 54 Bibliography………………………………………………………… 55 | |
dc.language.iso | en | |
dc.title | 分子片段組合之新穎結構設計於抗血管內皮生長因子受體藥物開發 | zh_TW |
dc.title | A Fragment-based De Novo Design of VEGFR2/3 Inhibitors | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 歐陽明,郭明良,孫仲銘 | |
dc.subject.keyword | 血管內皮生長因子受體,基於片段,新穎結構設計,片段效率,第二型磷酸激酶,抑制劑, | zh_TW |
dc.subject.keyword | VEGFR,Fragment-based,De-Novo Design,Group Efficiency,Type II Kinase Inhibitors, | en |
dc.relation.page | 58 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-08-17 | |
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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