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 CHENChen D.-S.Liaw S.-H.Chern J.-W.2021-07-032021-07-0320090022-2623https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984532074&doi=10.1021%2fjm8011905&partnerID=40&md5=fd401a4d0972c2e4c6d2702cbd9a1333https://scholars.lib.ntu.edu.tw/handle/123456789/568580Hepatitis 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.[SDGs]SDG34 [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 relationjournal article10.1021/jm8011905194192032-s2.0-84984532074