以電腦模擬探討腸病毒71型在VP1與3C蛋白酶上的抑制劑研究

Study of VP1 and 3C Protease for Enterovirus 71 for inhibitor’s binding site

林明粲(LIN MING TSAN)

指導教授 ： 李正宇

亞洲大學/資訊學院/生物資訊學系碩士班/碩士(2009年)

摘要

十一年前台灣曾爆發腸病毒的大流行，造成十三萬名的通報病例，78名孩童死亡，405名孩童引發嚴重的併發症。之後，每年台灣都還有傳出腸病毒71型 (Enterovirus 71) 的病例，而至今仍還未研發出有效抑制腸病毒71型的抑制劑。
隨著近年來計算機的進步以及生物資訊 (Bioinformatics) 的發展，利用電腦模擬配合生物科技或分子醫學相關的知識及應用，以同源模擬 (homology modeling) 的方法可模擬出腸病毒71型的外鞘蛋白VP1 (capsid _VP1)及3C蛋白酶(3C_ protease)的三維立體結構，再利用分子嵌合軟體 AutoDock 與文獻中找出的 Ligand進行嵌合計算。針對分子嵌合後的結合位置做分析，計算出平衡結合能及抑制常數Ki等能量值，以及分析病毒蛋白與Ligand之間的氫鍵作用力，氫鍵在分子結合過程中也是非常重要的參考依據。
研究結果得到Ligand 4有不錯的表現力，並且可取代VP1上的類脂肪分子穿過疏水性凹槽與VP1結合，而Ligand AG7088與3C蛋白酶也有不錯的表現力，未來可利用研究結果以實驗方式找出可能抑制腸病毒71型的前導藥物。

關鍵字

HASH(0x8bf91a4) ； HASH(0x8bf921c) ； HASH(0x8bf9294)

並列摘要

It has been a highly prevalent Enterovirus 71 epidemic disease in Taiwan, The disease brought about 130,000 notification cases, causing 78 children to die and 405 children infected the complication between 1998 and 2000. The Enterovirus 71 infection unceasingly happens every year in Taiwan; however, the researchers had not found out the Enterovirus 71 inhibitor which could effectively control the virus today.
Recently, due to the computer technique and Bioinformatics development, one can use computer simulation, combining with biotechnology and molecular medicine related knowledge and applications. The method may create three dimensional structures by simulating the capsid_VP1 and the 3C_ protease of Enterovirus 71 with homology modeling, and using the software of molecular docking with AutoDock to search the ligands which can be found in the literatures. After analyzing the molecular docking binding site, we can find balanced energy contents, binding energies, and inhibition constant Ki, as well as the interactions between the virus protein and the ligands with hydrogen bonds, and the hydrogen bonds in the molecular union process also give an important reference.
The result appears that Ligand_4 has the good expressive force, and it may substitute lipids above lipoid membranes in the VP1 to pass through the hydrophobic cavities unifying the VP1, and the interactions between the ligand_AG7088 and the 3C_protease have a good expressive force. We could use this to investigate the leader medicines of possibly suppress Enteritis 71 by experiments in the future works.

並列關鍵字

Enterovirus 71 ； homology modeling ； Molecular docking ； AutoDock

參考文獻

[1]台灣行政院衛生署疾病管制局URL:http://www.cdc.gov.tw/

[2] Gilbert G.L., Dickson K.E., and Waters M.J. et al. Outbreak of enterovirus 71 in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr. Infect. Dis. J. 7:484-488. (1988)

[3] Blomberg J., Lycke E., Ahlfors K., Johnsson T., Wolontis S., and von Zeipel G. New enterovirus type associated with epidemic of aseptic meningitisand/or hand, foot, and mouth disease. Lancet. 2:112. (1974)

[4] Lin T-Y, Twu S- J, Ho M-S, Chang L-Y, Lee C-Y. Enterovirus 71 outbreaks, Taiwan : occur rence and recognition.

Emerg Infect Dis. (2003) Available from: