臺灣博碩士論文加值系統

本篇論文利用分子對接 (Docking) 與分子動力模擬 (Molecular Dynamics, MD) 探討中藥分子與麩氨酸受體以及環氧合酶這兩種蛋白質的作用。我們從中藥溫清飲 (WenQingYin) 中依據結構的不同選擇了四種中藥分子，分別是 2-(3,4-dihydroxyphenyl)-5,6,7-trihydroxy-4H-chromen-4-one (PHF), 4-hydroxy-3-methoxybenzoic acid (HMB), 4-(2,3-dihydroxy-3-methylbutoxy)-7H-furo[3,2-g]chromen-7-one (DHMBP) 以及 methyl 7-formylcyclopenta[c]pyran-4-carboxylate (cerbinal)，分別模擬了四種不同的藥物分子在兩種蛋白質上的作用情形。
在麩氨酸受體系統所得到的結果顯示，PHF、HMB 及 DHMBP 分子會與 GluR2 蛋白質中活性位置的胺基酸產生氫鍵，並形成穩定的複合體結構； cerbinal 分子和 GluR2 蛋白質沒有產生氫鍵，並且使得 GluR2 蛋白質結構發生改變。在環氧合酶系統所得到的結果顯示，PHF、DHMBP 及 cerbinal 分子會與 COX-2 蛋白質中活性位置的胺基酸產生氫鍵，並穩定存在環氧合酶活性位置中。利用分子對接和分子動力學模擬的結果能知道中藥分子和蛋白質之間的實際相互作用情形，這有助於了解中藥分子在蛋白質中的效果，並對於蛋白質拮抗劑與抑制劑的開發，以及中藥分子的研究領域能有更進一步的了解。

Molecular docking and molecular dynamics (MD) simulations have been carried out to investigate the interaction of a traditional Chinese medicine (TCM), WenQingYin, with the glutamate receptor 2 (GluR2) and cyclooxygenase-2 (COX-2). Four representative drug components of TCM molecules, namely 2-(3,4-dihydroxyphenyl)-5,6,7-trihydroxy-4H-chromen-4-one (PHF), 4-hydroxy-3-methoxybenzoic acid (HMB), 4-(2,3-dihydroxy-3-methylbutoxy)-7H-furo[3,2-g]chromen-7-one (DHMBP) and methyl 7-formylcyclopenta[c]pyran-4-carboxylate (cerbinal), and their complexes with GluR2 and COX-2 were simulated.
In GluR2 systems, our results show that PHF, HMB and DHMBP formed a partial hydrogen bond with GluR2 in its ligand-binding domain. However, cerbinal was not stable in the ligand-binding domain of GluR2 and induced a significant change in the structure of GluR2. Three-dimensional plots represent the contact and movement situation of the TCM molecules in the ligand-binding domain of GluR2. In COX-2 systems, our results show that PHF, DHMBP and cerbinal were stable and formed a partial hydrogen bond with its active site. However, the hydrogen bonds are formed on HMB in docking but not observed in MD simulation. It shows that the HMB have an unstable interaction with COX-2.
The interaction between drugs and proteins is a major factor influencing the drug efficacy. The stability of drugs in the active site affects the activity of the protein. Our results suggest that PHF, HMB and DHMBP are considered to be GluR2 antagonists; PHF, DHMBP and cerbinal are considered to be COX-2 inhibitors. The combined results of the docking and molecular dynamics simulations provide insight into the interaction between these traditional Chinese medicine molecules and proteins.

論文審定書 ................................................................................................................... i
論文公開授權書 .......................................................................................................... ii
誌謝 ......................................................................................................................... iii
摘要 ......................................................................................................................... iv
Abstract ........................................................................................................................ v
Table of Contents ........................................................................................................ vii
List of Figures ............................................................................................................... x
List of Tables .............................................................................................................. xiv
Chapter 1 Introduction ............................................................................................. 1
1.1 Traditional Chinese Medicine .......................................................................... 3
1.2 AMPA Receptor ............................................................................................... 5
1.3 Cyclooxygenase .............................................................................................. 8
1.4 WenQinYing .................................................................................................. 11
Chapter 2 Computer Simulation Method ................................................................ 12
2.1 Molecular Docking ........................................................................................ 13
2.1.1 AutoDock Program ............................................................................................. 16
2.2 Molecular Dynamics Simulation .................................................................... 18
2.2.1 Equations of Motion and Verlet Leapfrog Integration ......................................... 18
2.2.2 Force Field ......................................................................................................... 19
2.2.3 Thermodynamic Ensembles ................................................................................ 22
2.2.4 Periodic Boundary Condition .............................................................................. 23
2.2.5 Root Mean Square Deviation and Radial Distribution Function ........................... 24
2.2.6 AMBER Program ............................................................................................... 26
Chapter 3 The Conformation of Proteins in Aqueous Solution ................................ 28
3.1 Introduction ................................................................................................... 28
3.2 Method .......................................................................................................... 29
3.3 Conformational Change of GluR2 in Aqueous Solution ................................. 31
3.4 Conformational Change of COX-2 in Aqueous Solution ................................ 34
3.5 Summary ....................................................................................................... 36
Chapter 4 The Interaction between TCM Molecules and Proteins by Molecular Docking ............................................................................................................. 37
4.1 Introduction ................................................................................................... 37
4.2 Method .......................................................................................................... 40
4.3 The Binding Orientation of TCM Molecules to GluR2................................... 41
4.4 The Binding Orientation of TCM Molecules to COX-2 ................................. 43
4.5 Summary ....................................................................................................... 49
Chapter 5 The Interaction between TCM Molecules and Proteins by Molecular Dynamics Simulation ................................................... 50
5.1 Introduction ................................................................................................... 50
5.2 Method .......................................................................................................... 52
5.3 The Interaction between TCM Molecules and GluR2 ..................................... 54
5.3.1 The TCM Molecules in the Active Site of GluR2 ................................................ 54
5.3.2 The Conformational Change of GluR2 ................................................................ 58
5.3.3 The Interaction of Drug–GluR2 Complexes ........................................................ 59
5.3.4 The Movement of TCM Molecules in the Ligand-Binding Domain ..................... 62
5.3.5 The Conformational Change of Cerbinal–GluR2 Complex .................................. 65
5.4 The Interaction between TCM Molecules and COX-2.................................... 67
5.4.1 The TCM Molecules in the Active Sites of COX-2 ............................................. 67
5.4.2 The Conformational Change of COX-2 ............................................................... 69
5.4.3 The Interaction of Drug–COX-2 Complexes ....................................................... 69
5.5 Summary ....................................................................................................... 72
Chapter 6 Conclusion ............................................................................................. 74
References .................................................................................................................. 76

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