Identification of novel inhibitors of HCV RNA-dependent RNA polymerase by pharmacophore-based virtual screening and in vitro evaluation

Kisun Ryu, Nam Doo Kim, Seong Il Choi, Cheol Kyu Han, Jeong Hyeok Yoon, Kyoung Tai No, Kyun Hwan Kim, Baik L. Seong

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32 Citations (Scopus)


Hepatitis C virus (HCV) is the major etiological agent of non-A, non-B hepatitis where no effective treatment is available. The HCV NS5B with RNA-dependent RNA polymerase (RdRp) activity is a key target for the treatment of HCV infection. Here we report novel NS5B polymerase inhibitors identified by virtual screening and in vitro evaluation of their inhibitory activities. On the basis of a newly identified binding pocket of NS5B, distinct from the nucleotide binding site but highly conserved among various HCV isolates, we performed virtual screening of compounds that fit this binding pocket from the available chemical database of 3.5 million compounds. The inhibitory activities of the in silico selected 119 compounds were estimated with in vitro RdRp assay. Three compounds with IC50 values of about 20 μM were identified, and their kinetic analyses suggest that these compounds are noncompetitive inhibitors with respect to the ribonucleotide substrate. Furthermore, the single-point mutations of the conserved residues in the binding pocket of NS5B resulted in the significant decrease of the RdRp activity, indicating that the binding pocket presented here might be important for the therapeutic intervention of HCV. These novel inhibitors would be useful for the development of effective anti-HCV agents.

Original languageEnglish
Pages (from-to)2975-2982
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number8
Publication statusPublished - 2009 Apr 15

Bibliographical note

Funding Information:
This work was supported in part by the Korea Science and Engineering Foundation (KOSEF) Grant (Grant No. 2007-04384), the Korea Research Foundation Grant (Grant No. KRF-2004-005-C00148), and Second-phase of BK21 Project in 2009 (to K.H. Kim) by the Korean Government.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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