以電腦模擬來探討瘧疾的BP2 與VP2半胱胺酸蛋白酶的抑制劑研究

Study of inhibitors for BP2 and VP2 cysteine proteases

卓育生(Yu-sheng Cho)

指導教授 ： 李桂仁

亞洲大學/資訊學院/生物資訊學系碩士班/碩士(2009年)

摘要

瘧疾是一種潛在致命的疾病，它是由瘧原蟲(plasmodium)所引起
的急性傳染病，瘧疾的名稱是源自於義大利文(malaria)，意思是「不
好的空氣」，多發生於溫暖潮濕的熱帶地區，瘧蚊(Anopheles)為其傳
播媒介，根據世界衛生組織報導，瘧疾目前存在於100 多個國家中，
大多是撒哈拉以南的非洲地區和東南亞地區，全球每年大約有3 億多
件關於瘧疾的案例，而有150 多萬人死於該病。近年來電腦硬體及軟
體的快速發展，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)的方法可以模擬出同為鼠瘧蛋
白的BP-2(berghepain-2)和VP-2 (vinckepain-2)的3D 立體結構，再利
用分子嵌合軟體AutoDock 與文獻中找到的Ligand 進行分子嵌合運算，
針對分子嵌合後的結合位置做分析，計算出預測的結合自由能
(Estimated Free Energy of Binding)與抑制常數ki(inhibitory constant)，
以及分析病毒蛋白與Ligand 之間的氫鍵作用力。經過電腦模擬計算
後發現Ligand 1 對BP-2 與Ligand 4 對VP-2 有不錯的表現，預測的
結合自由能與抑制常數Ki 都是最低，利用此研究結果可提供未來發
展新藥的思考方向。

關鍵字

瘧疾 ； 分子嵌合 ； 同源模擬

並列摘要

Malaria is a potentially fatal disease, and is an acute infectious disease caused by the malaria parasites. The name malaria comes from Italian (malaria), which means "bad air". Malaria usually occurs in warm and humid tropical regions. This disease is transferred by the malaria mosquitoes (anopheles) . According to World Health Organization report, malaria exists in more than 100 countries, most Saharan Africa and South-East Asia. Every year, more than 300 million of malaria cases occur on the world, and more than 150 million people died due to the disease. In recent years, because of the rapid development of computer hardware and software, we can use computer-simulated molecular medicine or biotechnology-related knowledge and application to develop new drugs. Protein structures constructed by homology modeling methods can be used to simulate malaria proteins for BP-2 (berghepain-2) and VP-2 (vinckepain-2) of the three-dimensional structure. Using the AutoDock of the molecular docking software with ligands found in the literature to perform the molecular docking computing. The analysis was based on the ligands binding site and we can calculate binding Free Energy and inhibition constant ki. By analysis of the hydrogen bonds between Ligands and proteins, it can be found that Ligand 1 on BP-2 and Ligand 4 on VP-2 have good results by the lowest values of estimated binding free energies and inhibition constants ki. The results of this study may provide a direction for developing new drugs.

並列關鍵字

berghepain ； vinckepain ； Homology modeling

參考文獻

Molecular modeling software and methods for medicinal chemistry

J. Med. Chem., 1990, 33 (3), pp 883–894

Recent developments in structural proteomics for protein structure determination

Proteomics. 2005 May;5(8):2056-68

Fighting an Ancient Scourge;