https://scholars.lib.ntu.edu.tw/handle/123456789/568580
標題: | Structure-based discovery of triphenylmethane derivatives as inhibitors of hepatitis C virus helicase | 作者: | Chen C.-S. Chiou C.-T. Chen G.S. Chen S.-C. Hu C.-Y. Chi W.-K. Chu Y.-D. Hwang L.-H. PEI-JER CHEN Chen D.-S. Liaw S.-H. Chern J.-W. |
公開日期: | 2009 | 出版社: | American Chemical Society | 卷: | 52 | 期: | 9 | 起(迄)頁: | 2716-2723 | 來源出版物: | Journal of Medicinal Chemistry | 摘要: | Hepatitis C virus nonstructural protein 3 (HCV NS3) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. A fluorescence resonant energy transfer helicase assay was established for fast screening of putative inhibitors selected from virtual screening using the program DOCK. Soluble blue HT (1) was first identified as a novel HCV helicase inhibitor. Crystal structure of the NS3 helicase in complex with soluble blue HT shows that the inhibitor bears a significantly higher binding affinity mainly through a 4- sulfonatophenylaminophenyl group, and this is consistent with the activity assay. Subsequently, fragment-based searches were utilized to identify triphenylmethane derivatives for more potent inhibitors. Lead optimization resulted in a 3-bromo-4-hydroxyl substituted derivative 12 with an EC50 value of 2.72 μ M to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC50) 10.5 μM), and it indeed suppressed HCV replication in the HCV replicon cells. Therefore, these inhibitors with structural novelty may serve as a useful scaffold for the discovery of new HCV NS3 helicase inhibitors. ? 2009 American Chemical Society. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984532074&doi=10.1021%2fjm8011905&partnerID=40&md5=fd401a4d0972c2e4c6d2702cbd9a1333 https://scholars.lib.ntu.edu.tw/handle/123456789/568580 |
ISSN: | 0022-2623 | DOI: | 10.1021/jm8011905 | SDG/關鍵字: | 4 [1 (3 bromo 4 hydroxyphenyl) 1 [4 [2 (3 bromo 4 ydroxyphenyl)propan 2 yl]phenyl]ethyl] 2 bromophenol; antivirus agent; helicase; helicase inhibitor; triphenylmethane derivative; unclassified drug; antiviral activity; article; controlled study; drug screening; enzyme inhibitor interaction; Hepatitis C virus; human; human cell; IC 50; structure activity relation |
顯示於: | 臨床醫學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。