Structure-based discovery of triphenylmethane derivatives as inhibitors of hepatitis C virus helicase

Chien Shu Chen, Chun Tang Chiou, Grace Shiahuy Chen, Sheng Chia Chen, Chih Yung Hu, Wei Kuang Chi, Yi Ding Chu, Lih Hwa Hwang, Pei Jer Chen, Ding Shinn Chen*, Shwu Huey Liaw, Ji Wang Chern

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish
Pages (from-to)2716-2723
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - 14 May 2009


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