Structure-based discovery of triphenylmethane derivatives as inhibitors of hepatitis C virus helicase.
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 EC(50) value of 2.72 microM to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC(50) = 10.5 microM), 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.
Chen
Chien-Shu
CS
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chiou
Chun-Tang
CT
Chen
Grace Shiahuy
GS
Chen
Sheng-Chia
SC
Hu
Chih-Yung
CY
Chi
Wei-Kuang
WK
Chu
Yi-Ding
YD
Hwang
Lih-Hwa
LH
Chen
Pei-Jer
PJ
Chen
Ding-Shinn
DS
Liaw
Shwu-Huey
SH
Chern
Ji-Wang
JW
D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects; D012984:Software; D014320:Triphenylmethyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D011480:Protease Inhibitors; D014320:Triphenylmethyl Compounds; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C046945:triphenylmethane