Identification of ligands that target the HCV-E2 binding site on CD81

Reem Al Olaby, Hassan M. Azzazy, Rodney Harris, Brett Chromy, Jost Vielmetter, Rod Balhorn

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Hepatitis C is a global health problem. While many drug companies have active R&D efforts to develop new drugs for treating Hepatitis C virus (HCV), most target the viral enzymes. The HCV glycoprotein E2 has been shown to play an essential role in hepatocyte invasion by binding to CD81 and other cell surface receptors. This paper describes the use of AutoDock to identify ligand binding sites on the large extracellular loop of the open conformation of CD81 and to perform virtual screening runs to identify sets of small molecule ligands predicted to bind to two of these sites. The best sites selected by AutoLigand were located in regions identified by mutational studies to be the site of E2 binding. Thirty-six ligands predicted by AutoDock to bind to these sites were subsequently tested experimentally to determine if they bound to CD81-LEL. Binding assays conducted using surface Plasmon resonance revealed that 26 out of 36 (72 %) of the ligands bound in vitro to the recombinant CD81-LEL protein. Competition experiments performed using dual polarization interferometry showed that one of the ligands predicted to bind to the large cleft between the C and D helices was also effective in blocking E2 binding to CD81-LEL.

Original languageEnglish (US)
Pages (from-to)337-346
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Volume27
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • AutoDock
  • CD81 receptor
  • Dual polarization interferometry
  • HCV glycoprotein E2
  • Hepatitis C virus
  • Surface plasmon resonance
  • Viral entry inhibitors

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

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  • Cite this

    Olaby, R. A., Azzazy, H. M., Harris, R., Chromy, B., Vielmetter, J., & Balhorn, R. (2013). Identification of ligands that target the HCV-E2 binding site on CD81. Journal of Computer-Aided Molecular Design, 27(4), 337-346. https://doi.org/10.1007/s10822-013-9649-3