臺灣博碩士論文加值系統

第五型磷酸二酯酵素 (PDE5) 在細胞中扮演著調控cGMP濃度的重要角色，與男性陽痿有直接的相關性。Tadalafil，也稱為犀力士 (Cialis®)，是一個β-carbolin衍生物能夠專一的抑制第五型磷酸二酯酵素的活性。對於52個β-carbolin衍生物，利用三維定量構效關係 (3D-QSAR) 的方法來分析描述此類藥物的活性與結構之間的定量關係。利用Catalyst及CoMFA這兩套軟體來分析31個位於訓練組的化合物以建立兩個三維定量構效關係的電腦模型；另一方面，則利用21個位於測試組中的化合物以確定此電腦模型的可信度。經由比較生物體外實驗與電腦模型預測的結果分析得知，Catalyst及CoMFA所得到的電腦模型皆具有相當高的預測性。Catalyst方面，相關係數高達0.816，藥效基團模型包括一個氫鍵的提供者、兩個氫鍵的接受者以及一個疏水性作用區；CoMFA所建立的分子力場模型則具有4個要素並且得到相關係數為0.945，在測試組也得到0.810的高相關性。經過比對兩個電腦模型的結果得知一個氫鍵提供者以及另外有兩個氫鍵接受者，對於此類化合物在第五型磷酸二酯酵素的抑制作用上，扮演一個相當重要的角色。進一步地，利用LigBuilder程式來建立一個以犀利士為先導藥物的虛擬化合物資料庫，總共產生了200個新生藥物。我們便利用先前所建立的兩個電腦模型來重新評分這200新生的化合藥物，除此之外，我們再利用SCORE及AutoDock這兩個評分函數來加以評分，我們從中得到 11個候選藥物位於三個評分函數的前50名，因此可做為新一代藥物開發的研究目標。我們建立了一個PDE5-DDDB線上資料庫。此資料庫提供了所有與虛擬化合物資料庫相關的資訊。而此資料庫提供了一個相當方便的平台讓研究PDE5和抑制物交互關係的研究者或是藥物發展的研發者更加容易取得此虛擬資料庫的相關訊息。

Phosphodiesterase type 5 (PDE5) is an important enzyme for controlling the levels of the intracellular cGMP which significantly corresponds to male erection dysfunction. Tadalafil, also known as Cialis, is a β-carboline derivative which inhibits PDE5 specifically. Three-dimensional quantitative structure-activity relationship (3D-QSAR) approach was used to construct pharmacophore models for a series of β-carboline derivative inhibitors of PDE5. The models generated using Catalyst and CoMFA packages with a training set of 31 molecules were confirmed by the test set of 21 molecules. The high r2 value (0.816) between the predicted and observed activity showed that the Catalyst pharmacophore hypothesis was predictive. This hypothesis contained four features, including a hydrogen bond donor, two hydrogen bond acceptors and a hydrophobic feature. The CoMFA model consisted of four components with an r2 of 0.945 and produced good predictions for test set (r2 = 0.810). Comparison between these two models, two hydrogen bond acceptors and one hydrogen bond donor were found to contribute significantly to the inhibition activities of β-carboline derivatives. LigBuilder package was used to establish a new drug library. Totally 200 compounds were generated and rescored by using 3D-QSAR models and two scoring functions, SCORE and AutoDock. Eleven drugs were selected and thought as candidates for further analysis because of ranked among top fifty for at least three rescoring functions. PDE5-Drug Development Database (PDE5-DDDB) has been built up as a friendly platform for study of PDE5-inhibitor interactions, which archives information of new drugs.

Contents 1
Contents of Tables and Figures 2
Abstract 3
摘要 4
Abbreviation 5
Chapter 1. Introduction 6
1.1 Male erectile dysfunction 6
1.2 Phosphodiesterase 6
1.3 Inhibitors of PDE5 8
1.4 3D-QSAR 9
1.5 The Theme of This Thesis 9
Chapter 2. Materials & Methods 12
2.1 Data Sets 12
2.2 Molecular Modeling 13
2.3 Modeling with Catalyst HypoGen Module 13
2.4 Validation of Catalyst Model. 14
2.5 Modeling with Sybyl CoMFA Module 15
2.6 Examining the predictive ability of CoMFA model. 16
2.7 Virtual Drug Library Construction 17
2.8 Consensus Scoring: Definition of a Hit List 17
2.9 Database Construction 19
Chapter 3. Result and Discussion 21
3.1 Catalyst HypoGen pharmacophore modeling 21
3.2 Pharmacophore Cross-Validation Study 23
3.3 CoMFA 3D-QSAR modeling 24
3.4 Validation of hypotheses Using Test Set Compounds. 26
3.5 Comparison between two models 28
3.6 Virtual drug library 29
3.7 Definition of a Hit List 30
3.8 PDE5-DDDB 31
Chapter 4. Conclusion 33
References 35
Appendix 1. 58
Appendix 2. 59

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