臺灣博碩士論文加值系統

過去的研究指出，人類表皮生長因子受體2 (HER2) 的過表達與乳癌的發生有所關聯，因此，HER2被認為是一個可以用來治療乳癌的藥物標靶。目前，已經開發出許多可逆性HER2抑制劑用來治療HER2陽性乳癌 ，其中的lapatinib (Tykerb®) 已經通過美國食品藥物管理局的審查。然而HER2上的三種點突變 (L755S、T798I、T798M) 已被證實會對lapatinib產生耐藥性。雖然已有一些不可逆性HER2抑制劑被開發出來用於克服這些耐藥性問題，然而，大部分都還停留在臨床試驗階段。因此，為了尋找更有效且副作用較低的新型不可逆性HER2抑制劑，我們應用了數種電腦演算方法，包含以結構為基礎的藥效基團模型、虛擬篩選、分子嵌合、分子動態模擬與ADMET分析。我們依據HER2 L755S、T798I、T798M三種突變的同源結構模型，分別建構三種以結構為基礎的藥效基團模型，並且藉由receiver operating characteristic (ROC)曲線分析與Güner-Henry (GH) 評分方法進行驗證。根據驗證結果，最佳的藥效基團模型將作為3D模板，從美國國家癌症研究所的小分子資料庫中進行虛擬篩選，其中能吻合所有藥效基團模型結構特徵及具有不可逆性抑制劑必要結構 Michael acceptor的小分子將被篩選出來，作為具潛力的不可逆性HER2抑制劑。接下來以分子嵌合模擬來分析其位於結合位點的結合作用力，根據分子嵌合評分函數與分子嵌合構型，我們挑選出NSC278329、NSC642003、NSC718305三個分子作為不可逆HER2抑制劑。最後，我們利用分子動態模擬的實驗來驗證HER2的突變結構和這三種不可逆抑制劑之間的結合是穩定的。為了降低臨床失敗的風險，我們還進行了ADMET分析。在ADMET分析結果中發現，由於NCS642003的高致癌性與對CYP450的高抑制性，使其不適合臨床使用。最後，只有NSC278329和NSC718305被我們認為是具安全性的新型不可逆HER2抑制劑，這兩個分子可在未來進行體外/體內分析，以評估其藥效或作為先導化合物來設計更有效的不可逆HER2抑制劑。

Previous studies have indicated that overexpression of human epidermal growth factor receptor 2 (HER2) is associated with the carcinogenesis of breast cancer. Therefore, HER2 has been considered as a drug target for breast cancer treatment. So far, many reversible HER2 inhibitors have been developed for treating HER2-positive breast cancer. Among them, lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA). However, three types of HER2 point mutations, including L755S, T798I and T798M, have been shown to confer drug resistance toward lapatinib. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them are still under clinical trials. Therefore, several computational approaches, including structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics simulation and ADMET analysis, were adopted in this study to discover novel irreversible HER2 inhibitors with better efficacy and less side effects. Three different pharmacophore models were constructed based on the built homology models of HER2 L755S, T798I and T798M. These models were subsequently validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Then, the best models were utilized as 3D queries to screen compounds from the National Cancer Institute (NCI) database. Only compounds which fit well with all the features of the pharmacophore models and show the covalent interaction termed as Michael acceptor, an essential substructure of irreversible inhibitors, were retrieved as hit compounds. Then, they were submitted to molecular docking experiments to investigate their binding interactions in their respective binding pockets. Based on the docking scores and docking poses, three compounds, NSC278329, NSC642003 and NSC718305, were selected as the potential irreversible HER2 inhibitors. Finally, these three binding complexes were subjected to molecular dynamics (MD) simulations and the results showed that these binding complexes were stable during the entire MD simulation courses. To reduce the risk of clinical failure, ADMET analyses were performed towards these three compounds and the results showed that NCS642003 exhibited high carcinogenicity and CYP450 inhibitory promiscuity, making it unsuitable for clinical use. Finally, only NSC278329 and NSC718305 were considered as safe and novel irreversible HER2 inhibitors, which can be further subjected to in vitro/vivo analyses to estimate their efficacy or the possibility to act as the lead compounds for designing more potent irreversible HER2 inhibitors.

CHINESE ABSTRACT...i
ENGLISH ABSTRACT...iii
ACKNOWLEDGEMENTS...v
CONTENTS...vi
TABLE CONTENTS...viii
FIGURE CONTENTS...ix
Chapter 1 GENERAL INTRODUCTION...1
Chapter 2 LITERATURE REVIEW...3
2.1 Breast cancer...3
2.2 Human epidermal growth factor receptor 2...4
2.3 The development of anti-HER2 drugs...4
2.4 The mutations and variants of HER2...5
2.5 The development of irreversible HER2 inhibitors...11
Chapter 3 Methods...13
3.1 Overview...13
3.2 Pharmacophore modeling...14
3.2.1 HypoGen pharmacophore...15
3.2.2 Receptor-ligand pharmacophore...15
3.3 Virtual screening...16
3.4 Molecular docking...17
3.4.1 Docking programs...18
3.5 Molecular dynamics simulations...18
3.5.1 Force field...19
3.5.1.1 CHARMm force field...19
3.5.1.2 The Parameters in the force field...20
3.5.1.3 Functional form of the CHARMm Force Field...23
3.5.2 Minimization...24
3.5.3 Equilibrium...27
3.5.4 Molecular dynamics...28
Chapter 4 Discovery of novel irreversible HER2 inhibitors for breast cancer treatment...30
4.1 Abstract...30
4.2 Introduction...30
4.3 Materials and Methods...32
4.3.1 Protein and ligand preparation...32
4.3.2 Structure-based pharmacophore model generation and validation...34
4.3.3 Virtual screening and molecular docking...35
4.3.4 Molecular dynamics (MD) simulation...37
4.3.5 ADMET analysis...37
4.4 Results and discussion...37
4.4.1 Structure-based pharmacophore model generation and
validation...38
4.4.2 Virtual screening and molecular docking...43
4.4.3 MD simulations...47
4.4.4 ADMET analysis...48
4.4.5 Evaluation of hit compounds...50
4.5 Conclusions...52
4.6 References...53
Chapter 5 GENERAL CONCLUSION...58
Chapter 6 GENERAL REFERENCE...59

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