Identification of novel target sites and an inhibitor of the dengue virus E protein

  • Ragothaman Yennamalli
  • Naidu Subbarao
  • Thorsten Kampmann
  • Ross P. McGeary
  • Paul R. Young
  • Bostjan Kobe
Article

DOI: 10.1007/s10822-009-9263-6

Cite this article as:
Yennamalli, R., Subbarao, N., Kampmann, T. et al. J Comput Aided Mol Des (2009) 23: 333. doi:10.1007/s10822-009-9263-6

Abstract

Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC50 in the micromolar range against dengue virus type 2.

Keywords

Dengue virus Envelope protein Flavivirus Virtual drug screening 

Abbreviations

BSA

Bovine serum albumin

DENV

Dengue virus

DMEM

Dulbecco’s modified Eagle’s medium

FCS

Fetal calf serum

JEV

Japanese encephalitis virus

MTT

Methyl thiazole tetrazolium

PDB

Protein Data Bank

PBS

Phosphate buffered saline

pfu

Plaque-forming units

TBEV

Tick-borne encephalitis virus

WNV

West Nile virus

Supplementary material

10822_2009_9263_MOESM1_ESM.doc (1.3 mb)
(DOC 1321 kb)

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ragothaman Yennamalli
    • 1
    • 2
  • Naidu Subbarao
    • 1
  • Thorsten Kampmann
    • 2
  • Ross P. McGeary
    • 2
  • Paul R. Young
    • 2
    • 3
  • Bostjan Kobe
    • 2
    • 3
  1. 1.Centre for Computational Biology and Bioinformatics, School of Information TechnologyJawaharlal Nehru UniversityNew DelhiIndia
  2. 2.School of Chemistry and Molecular BiosciencesUniversity of QueenslandBrisbaneAustralia
  3. 3.Institute for Molecular BioscienceUniversity of QueenslandBrisbaneAustralia