期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 22, 页码 6892-6905出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.09.023
关键词
HCV; NS 3-4A protease; Structure based drug design; Ligand docking; Virtual screening
资金
- Health and Labor Sciences Research Grants for Research on Hepatitis
- Ministry of Health, Labor and Welfare
- Program of Funding Research Centers for Emerging and Reemerging Infectious Diseases
- Ministries of Education, Culture, Sports, Science, and Technology, Japan
- RIKEN Structural Genomics/Proteomics Initiative (RSGI)
- National Project on Protein Structural and Functional Analyses
- Targeted Proteins Research Program (TPRP)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Grants-in-Aid for Scientific Research [21590837, 22659145, 21590832, 23390195, 22590724, 21590831, 24659359, 21659186, 21390226] Funding Source: KAKEN
Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (GENIUS), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC50 = 1-10 mu M including high selectivity index). The new inhibitors thus identified were modified, based on the docking models, and revealed preliminary structure-activity relationships. Moreover, the GENIUS in silico screening performance was validated by using an enrichment factor. We believe our designed scaffold could contribute to the improvement of HCV chemotherapy. (C) 2011 Elsevier Ltd. All rights reserved.
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