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研究生:陳建宇
研究生(外文):Chein-Yu Chen
論文名稱:由NCI資料庫虛擬篩選H1N1,H1N2與H1N7之多靶點藥物
論文名稱(外文):Multiple-target drug design for H1N1, H1N2, and H1N7 by virtual screening the NCI database
指導教授:陳語謙陳語謙引用關係
指導教授(外文):Yu-Chien Chen
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:生物科技學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:74
中文關鍵詞:H1N1虛擬篩選建構藥效基團假設廣效性抑制劑
外文關鍵詞:neuraminidasevirtual screeningpharmacophore hypothesis generation (HyPoGen)versatile inhibitor
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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.
總目錄
摘要………………………………………………………………….…...1
Abstract……………………………………………………………….…2
致謝………………………………………………………....……………3
總目錄…………………………………………………………………....4
表目錄.....................................……………………..………………....….5
圖目錄............................................…………………………………........6

1.簡介(Introduction)………………………………………………….7
2.方法與材料(Material and methods)………..…………...……...…….10
2-1 資料設定(Dataset)……………………………………………10
2-2 建構藥效基團假設(Pharmacophore hypotheses generation, HyPoGen)……………………….……………………………10
2-3 NCI資料庫之篩選(NCI database screening)…………13
2-4分子對接分析(Molecular docking study)………………….….13
2-5藥效基團交互作用關係之生成與比對(Interaction generation and pharmacophore comparison)………………………….. 17
3.結果與討論(Results and discussion)………………………...………18
3-1同源模擬之結果(The results of homology modeling)……...18
3-2藥效基團假設生成之結果(The results of pharmacophore hypotheses generation)….........................................................19
3-3分子對接分析之結果(The results of docking study)...………20
3-4 N1, N2與N7藥效基團比較分析之結果(Results of N1, N2, and N7 pharmacophore comparison analysis)…………………..23
4.結論(Conclusion)……………………………………………………24
5.參考文獻(References)........................................…………..…….........27
6.已發表之論文著作(Publications)…………………..………………...67
6-1 論文發表(Journal publications)….…………………….........67
6-2 研討會發表(Conference publications)……………………...72
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Chen, C. Y. C, “Discovery of novel inhibitors for c-Met by virtual screening and pharmacophore analysis,” J. Chin. Inst. Chem. Eng. 39, 617 (2008a).
Chen, C. Y. C, “Inhibiting the vascular smooth muscle cells proliferation by EPC and DPPC liposomes encapsulated magnolol,” J. Chin. Inst. Chem. Eng. 39, 407 (2008b).
Chen, C. Y. C. "Insights into the suanzaoren mechanism-From constructing the 3D structure of GABA-A receptor to its binding interaction analysis." J. Chin. Inst. Chem. Eng. 39, 663 (2008c).
Chen, C. Y. C, “A novel perspective on designing the inhibitor of HER2 receptor,” J. Chin. Inst. Chem. Eng. 39, 291 (2008d).
Chen, C. Y. C, “Chemoinformatics and pharmacoinformatics approach for exploring the GABA-A agonist from Chinese herb suanzaoren,” J. Chin. Inst. Chem. Eng. 40, 36 (2009a).
Chen, C. Y. C, “De novo design of novel selective COX-2 inhibitors: From virtual screening to pharmacophore analysis,” J. Chin. Inst. Chem. Eng. 40, 55 (2009b).
Chen, C. Y. C, “Pharmacoinformatics approach for mPGES-1 in anti-inflammation by 3D-QSAR pharmacophore mapping,” J. Chin. Inst. Chem. Eng. 40, 155 (2009c).
Cheung, C. Y., L. L. Poon, A. S. Lau, W. Luk, Y. L. Lau, K. F. Shortridge, S. Gordon, Y. Guan, and J. S. Peiris, “Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?” Lancet 360, 1831 (2002).
Collins, P. J., L. F. Haire, Y. P. Lin, J. Liu, R. J. Russell, P. A. Walker, J. J. Skehel, S. R. Martin, A. J. Hay, and S. J. Gamblin, “Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants,” Nature 453, 1258 (2008).
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Gehlhaar, D. K., G. M. Verkhivker, P. A. Rejto, C. J. Sherman, D. B. Fogel, L. J. Fogel, S. T. Freer, “Molecular Recognition of the Inhibitor AG-1343 by HIV-1 Protease: Conformationally Flexible Docking by Evolutionary Programming,” Chemistry & Biology 2, 317 (1995).
Hauge, S. H., S. Dudman, K. Borgen, A. Lackenby, and O. Hungnes, “Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08,” Emerg. Infect. Dis. 15, 155 (2009).
Ho, H. T., A. C. Hurt, J. Mosse, and I. Barr, “Neuraminidase inhibitor drug susceptibility differs between influenza N1 and N2 neuraminidase following mutagenesis of two conserved residues,” Antiviral. Res. 76, 263 (2007).
Kash, J. C., T. M. Tumpey, S. C. Proll, V. Carter, O. Perwitasari, M. J. Thomas, C. F. Basler, P. Palese, J. K. Taubenberger, A. Garcia-Sastre, D. E. Swayne, and M. G. Katze, “Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus,” Nature 443, 578 (2006).
Kobasa, D., S. M. Jones, K. Shinya, J. C. Kash, J. Copps, H. Ebihara, Y. Hatta, J. H. Kim, P. Halfmann, M. Hatta, F. Feldmann, J. B. Alimonti, L. Fernando, Y. Li, M. G. Katze, H. Feldmann, and Y. Kawaoka, “Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus,” Nature 445, 319 (2007).
Kurogi, Y. and O.F. Guner, “Pharmacophore modeling and three-dimensional database searching for drug design using catalyst,” Curr. Med. Chem. 8, 1035 (2001).
Kurogi, Y., K. Miyata, T. Okamura, K. Hashimoto, K. Tsutsumi, M. Nasu, and M. Moriyasu, “Discovery of novel mesangial cell proliferation inhibitors using a three-dimensional database searching method,” J. Med. Chem. 44, 2304 (2001).
Lu, W.J., Y.L. Chen, W.P. Ma, X.Y. Zhang, F. Luan, M.C. Liu, X.G. Chen, and Z.D. Hu, “QSAR study of neuraminidase inhibitors based on heuristic method and radial basis function network,” Eur. J. Med. Chem. 43, 569 (2008).
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Mukhtar, M. M., S. T. Rasool, D. Song, C. Zhu, Q. Hao, Y. Zhu, and J. Wu, “Origin of highly pathogenic H5N1 avian influenza virus in China and genetic characterization of donor and recipient viruses,” J. Gen. Virol. 88, 3094 (2007).
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Shie J. J., J. M, Fang, C.H. Wong, “A concise and flexible synthesis of the potent anti-influenza agents tamiflu and tamiphosphor,” Angew. Chem. Int. Ed. Engl. 47, 5788 (2008).
Shimbo, T., M. Kawachi, K. Saga, H. Fujita, T. Yamazaki, K. Tamai, and Y. Kaneda, “Development of a transferrin receptor-targeting HVJ-E vector,” Biochem. Biophys. Res. Commun. 364, 423 (2007).
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Takabatake, N., M. Okamura, N. Yokoyama, K. Okubo, Y. Ikehara, and I. Igarashi, “Involvement of a host erythrocyte sialic acid content in Babesia bovis infection,” J. Vet. Med. Sci. 69, 999 (2007).
Teramoto, R., and H. Fukunishi, “Consensus Scoring with Feature Selection for Structure-Based Virtual Screening” J. Chem. Inf. Model. 48, 288 (2008)
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