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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林榮信 | |
| dc.contributor.author | Che-Chia Chang | en |
| dc.contributor.author | 張哲嘉 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:46:04Z | - |
| dc.date.available | 2014-09-19 | |
| dc.date.copyright | 2012-09-19 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-20 | |
| dc.identifier.citation | Reference
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Clinical oncology 2010, 7 (9), 493-507. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63505 | - |
| dc.description.abstract | 肺癌的死亡率占所有癌症死亡率中的第一位，以非小細胞肺癌為主，
因為發現不易，且發現時已接近晚期，治療不易，傳統上是以不具選擇性 的癌症化療藥物來治療，但副作用大，治療的成效也不理想。表皮生長因 子受體在很多固癌裡有過度表現的情形，而在非小細胞肺癌的病人中也有 40∼80﹪會過度表現，因此被視為一藥物設計的重要標的。在2003 年， 美國的FDA 通過了第一個以表皮細胞生長因子受體蛋白酪氨酸激酶抑制 劑，可對體細胞的突變（取代白氨酸為精氨酸）L858R，在亞洲地區病人， 女性，不吸癌者有顯著良好的治療結果，然而此類藥物在施予幾個月後病 人皆會發展出抗藥性。鑒於新型藥物開發的迫切性，我們的目標是運用高 計算效率的藥效基團比對，對六百萬化合物資料庫進行篩選，以尋找不同 化學骨架的L858R 抑制劑。 | zh_TW |
| dc.description.abstract | Lung cancer is the first mortality rate of all carcinoma. The major part is Non--‐Small--‐Cell Lung Cancer(NSC--‐LC). The curative effect is not ideal for not easily diagnosis and almost in the late state when the tumor
was discovered. Pharmacotherapy of lung cancer traditionally is by chemotherapy, but the adverse effect is serious and the curative effect is not ideal. Epidermal growth factor receptor (EGFR), is over--‐expresed in many solid tumor including the non--‐small--‐cell lung cancer (NSC--‐LC) (40~80%). In 2003, the first epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib) was approved by food and drug administration (FDA) in America. Dramatic therapeutic effect was discovered in Asia patient, non--‐smoker and women and is highly related to EGFR L858R (substitution of leucine 858 to arginine). However, drug resistance is occurred in several months after administration of this kind ofdrug. For the imperious demand of the new drug development, our goal is to discovery different scaffold EGFR L858R inhibitor (other than 4-anilinoquinazoline of gefitinib) by using the high performance pharmacophore based virtual screening to six million chemical database. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:46:04Z (GMT). No. of bitstreams: 1 ntu-101-R97423020-1.pdf: 3911403 bytes, checksum: 045d57b7f3efafa9b290782d8d15fa2d (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審定書………………………………………….....……………………….v 誌謝……………………………………………………………..……………………....vi Figure list……………………………………………………………………………..vii Table list…………………………………………………………………………….…ix 中文摘要…………………………………………………………...………………...…xi Abstract…………………………………………………………….…………………xii Chapter 1: Introduction 1.1 The Role of EGFR in Non--‐Small Cell Lung Cancer……..1 1.2 Pharmacotherapy of Non--‐Small Cell Lung Cancer……….3 1.3 Pharmacophore Method in Drug Discovery……………..……5 1.4 Docking Theory and Virtual Screening..................7 1.5 Autodock with Robust Scoring Function……………………11 1.6 Solubility Prediction…………………………………………13 1.7 Ligand Efficiency………………………………………………14 1.8 Ligand Binding Assay……………………………………………15 Chapter 2: Material and Methods 2.1 Pharmacophore Method …………………………………………………………..19 2.1.1 Receptor--‐based pharmacophore……………………………………..19 2.1.2 Generation of three--‐dimensional chemical database………………...…22 2.2 AutoDock with Robust Scoring Function 2.2.1 Preparation of ligand files for docking……………………………..……....…23 2.2.2 Preparation of receptor files for docking…………………………………......23 2.2.3 Preparation of grid parameter files………………………………………….....24 2.2.4 Preparation of docking parameter files………………………………….....….25 2.3 Prediction of Solubility of Candidates from Virtual Screening………...….26 2.4 Molecular Dynamic Simulations 2.4.1 Preparation of coordinate files and topology files…………………......…..27 2.4.2 Minimization…………………………………………………………………….…..28 2.4.3 Equilibration…………………………………………………………………….…...29 2.4.4 Productionrun………………………………………………………………………..30 2.5 Fluorescence Assay………........................…………………………………….31 Chapter 3: Results and Discussion 3.1 Receptor--‐Based Pharmacophore……………………….…………………….32 3.1.1 Pharmacophore from 2ITZ (EGFR L858R/Gefitinib)…….........……....…….32 3.1.2 Pharmacophore from 2ITT (EGFR L858R/AEE‐788)……....…….......…..…34 3.1.3 Pharmacophore from 2ITU (EGFR L858R/AFN-741)…….........……..…….35 3.1.4 Pharmacophore from 2ITV (EGFR L858R/AMP‐PNP)……....……..….........37 3.2 Common Candidate Set from Pharmacophore-Based Screening….....….43 3.2.1 The result of screened candidate and pharmacophore modification…………………………………………………………………….......38 3.2.2 The result of candidate intersection………………………………….......……47 3.3 Rescore and Re--‐Dock with AutoDock4 Robust Scoring Function……..48 3.4 Validation of AutoDock Results by Molecular Dynamic Simulation.........66 3.5 Results of Fluorescence Assay……………………………………….....……….74 Chapter 4: Discussion and Conclusion…………………………………………77 | |
| dc.language.iso | en | |
| dc.subject | 虛擬篩選 | zh_TW |
| dc.subject | 藥效基團 | zh_TW |
| dc.subject | 非小細胞肺癌 | zh_TW |
| dc.subject | 強固評分函數 | zh_TW |
| dc.subject | 分子動力學 | zh_TW |
| dc.subject | Virtual Screening | en |
| dc.subject | Pharmacophore | en |
| dc.subject | Non-small cell lung cancer | en |
| dc.subject | Molecular dynamic simulation | en |
| dc.subject | Robust scoring function | en |
| dc.title | 運用藥效基團集虛擬篩選以探索表皮生長因子受體抑制劑之新化學結構 | zh_TW |
| dc.title | Virtual Screening of Large Libraries with Pharmacophore Ensemble to Identify New Chemical Skeletons for Inhibitors of L858R Mutant Epidermal Growth Factor Receptor for Treating Non-Small Cell Lung Cancers | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧記華,孫英傑,許世宜 | |
| dc.subject.keyword | 藥效基團,非小細胞肺癌,虛擬篩選,強固評分函數,分子動力學, | zh_TW |
| dc.subject.keyword | Pharmacophore,Non-small cell lung cancer,Virtual Screening,Robust scoring function,Molecular dynamic simulation, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-08-20 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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