臺灣博碩士論文加值系統

類風濕性關節炎（Rheumatoid arthritis: RA）是一種慢性炎症的疾病，除了影響生活品量和工作效率，也對患者產生消極的想法。目前的RA治療採用緩解疾病的抗風濕藥物（DMARDs）進行治療。儘管這些治療方法中的多數情況下都是有效的，但大多數患者會因為效力差或副作用或兩者都有的不愉快經歷。白細胞介素-6受體（Interleukin-6 receptor: IL6R）在RA的發病機制過程中具備重要性。在這項研究中，期望透過篩選的方式從中醫藥（Traditional Chinese medicine: TCM）找出抑制IL6R的化合物來發展治療RA的方式。篩選的過程是使用TCM Database @ Taiwan資料庫裡的中醫藥化合物以虛擬篩選的方式發展有效的IL6R抑制劑。 TCM 候選化合物Calycosin與IL6R蛋白具有有效結合的親和力。分子動力學模擬用於驗證蛋白質複合物與Calycosin之間相互作用的穩定性。分析結果表示， Calycosin在蛋白質複合體中會更加穩定。此外，Calycosin已知是當歸(Angelica sinensis)的成分之一，已被證明在治療類風濕性關節炎中具有重要的作用。因此，Calycosin可能是一種具備潛力的候選藥物，可用於進一步研究IL6R蛋白在抗類風濕性關節炎的藥物開發。

Rheumatoid arthritis (RA) is a chronic inflammatory disease that will affect quality of life and, working efficiency, and produce negative thoughts for patients. Current therapy of RA is treated with disease-modifying antirheumatic drugs (DMARDs). Although most of these treatment methods are effective, most patients still have an unpleasant experience either due to poor efficacy or side effects or both. Interleukin-6 receptor (IL6R) is important in the pathogenesis of RA. In this study, we would like to detect the potential candidates which inhibit IL6R against RA from traditional Chinese medicine (TCM). We use TCM compounds from the TCM Database@Taiwan for virtually screening the potential IL6R inhibitors. The TCM candidate compound, Calycosin, has potent binding affinity with IL6R protein. The molecular dynamics simulation was employed to validate the stability of interaction in the protein complex with Calycosin. The analysis indicates that protein complex with Calycosin is more stable. In addition, Calycosin is known to be one of the components of Angelica sinensis, which has been indicated to have an important role in the treatment of rheumatoid arthritis. Therefore, Calycosin is a potential candidate as lead compounds for further study in drug development process with IL6R protein against rheumatoid arthritis.

中文摘要 i
英文摘要 ii
總目錄 iv
表目錄 v
圖目錄 vi
第一章 前言 1
第二章 材料與方法 4
2.1. 對接和候選化合物篩選 4
2.2.分子動力學（MD）模擬 5
第三章 結果與討論 6
3.1. 分子對接和候選藥物的篩選結果 6
3.2.分子動力模擬的分析結果 7
第四章 結論 10
參考文獻 11
附錄: 發表著作 36

表目錄

表一、 以對接分數和其他條件作為篩選前二十名的候選藥物的準則。 20
 
圖目錄
圖一、 透過PONDR-Fit預測不定型結構，數值高於0.5表示結構較為不定型，關鍵胺基酸以紅線做為表示。 21
圖二、 Calycosin的化學結構式。 22
圖三、 Calycosin在IL6R受體結合位點的對接結果。H-bond用綠色和藍色虛線做為表示，π鍵則是以橙色線表示。 23
圖四、 Calycosin在IL6R結合位點以疏水性鍵結結合的對接結果。 24
圖五、 Calycosin 與IL6R的RMSD 分析圖 25
圖六、 分析由Gromacs生成的MD的軌跡分析結果: (a) 旋轉半徑，(b) MSD。 26
圖七、 分子動力模擬的過程中總能量的變化: (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 27
圖八、 分子動力模擬的過程中RMSF的變化: (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 28
圖九、 群聚分析的結果: (a) Calycosin蛋白複合體 (cutoff: 0.142 nm)，(b) 無配體結合的IL6R蛋白 (cutoff: 0.145 nm)。 29
圖十、 分子動力模擬的過程中，Calycosin與IL6R蛋白各別的重心之間的距離變化。 30
圖十一、 DSSP二級結構變化分析，Calycosin與IL6R蛋白各別的重心之間的距離變化。(a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 31
圖十二、 胺基酸間距分析(Mdmat analysis): (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 32
圖十三、 特徵向量分布圖: (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 33
圖十四、 特徵向量PC1與PC2的分布圖: (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 34
圖十五、 小分子通道的預測結果: (a) Calycosin蛋白複合體，(b) 無配體結合的IL6R蛋白。 35

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