由NCI資料庫虛擬篩選H1N1, H1N2與H1N7之多靶點藥物

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題名:	由NCI資料庫虛擬篩選H1N1, H1N2與H1N7之多靶點藥物 Multiple-target drug design for H1N1, H1N2, and H1N7 by virtual screening the NCI database
作者:	陳建宇;Chein-Yu Chen
貢獻者:	生命科學院生物科技學系碩士班
關鍵詞:	H1N1;虛擬篩選;建構藥效基團假設;廣效性抑制劑;neuraminidase;virtual screening;pharmacophore hypothesis generation (HyPoGen);versatile inhibitor
日期:	2009
上傳時間:	2010-09-29 12:06:52 (UTC+8)
摘要:	在2009年初，H1N1流感疫情自墨西哥爆發並擴至全世界，因此開發新型抑制劑來對抗此波疫情已是燃眉之急。在本研究中，我們使用目前最新的H1N1序列以同源模擬法模擬出目前為止最新的H1與N1的蛋白質結構。由Ramachandran圖可知，在H1結構上僅有1.28%落於非合理角度構型的區域上；在N1結構上也僅有3.4%。加上Verify Score plot判讀得知，H1與N1的模擬結構有相當高的可信度。NCI資料庫包含有365,602個已知結構的藥用化合物，在本研究中以虛擬篩選的方式由其中選出具有潛力的化合物︰NCI0624650, NCI0607158, NCI0605741, PROTOVERINE, NCI0605737 KANAMYCIN-C, NCI0608643, NCI0606258, and NCI0608650等九種。除此之外，新的N1結構在此虛擬平台上被發現對於oseltamivir具有抗藥性。另一方面我們也以N2與N7的蛋白質結構個別生成了藥效基團的交互作用圖，並與N1的藥效基團假設做比對，在此研究中探討了三者的差異，完成了混合型藥效基團模型。最後以此混合型藥效基團模型用以篩選NCI資料庫，找出了六個可能成為廣效性NA抑制劑的候選化合物。我們的研究對於H1N1當前之疫情控制及未來之疫情預防，都有指標性的貢獻。 An outbreak of H1N1 influenza in Mexico was occurred in 2009. To find out drugs for treating this epidemic is emergency. In this study, we have built the latest N1 and H1 structure model by homology modeling, which has high reliability by Verify Score plot. In Ramachandran plot, it shows only 1.28% and 3.4% out of the region of possible angle formations in N1 and H1 models, respectively. 365,602 compounds from NCI database have been screened by docking study of H1 and N1, respectively. And then, NCI0624650, NCI0607158, NCI0605741, PROTOVERINE, NCI0605737 KANAMYCIN-C, NCI0608643, NCI0606258, and NCI0608650 were suggested as potent dual target candidates from the docking studies. Moreover, the latest N1 structure was found that have drug resistance to oseltamivir. Additionally, we have also created the interaction maps in the active sites on the neuraminidase type2, and type7 (N2 and N7) protein structures, aiming at creating the combined map for N1, N2, and N7 to resolve the difference in the three NA types. The combined map was employed to NCI database screening, and 6 candidates were found to be useful potent versatile inhibitors for N1, N2 and N7.
顯示於類別:	[生物科技學系暨碩士班] 博碩士論文

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