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

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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.

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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

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Acknowledgments

We thank Drs Kolaskar and Kulkarni-Kale, University of Pune, India, for providing the coordinates of the structure of Japanese encephalitis virus E protein, and Charlie Huang for helpful discussions. This work was funded by a grant from the National Health and Medical Research Council (NHMRC, Australia) to PRY and BK. BK is an Australian Research Council (ARC) Federation Fellow and NHMRC Honorary Research Fellow. RY was a recipient of the 2006 Endeavour Australia Cheung Kong Award for Asian Scholars and was supported by a Research Fellowship from the Indian Council of Medical Research.

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Authors and Affiliations

  1. Centre for Computational Biology and Bioinformatics, School of Information Technology, Jawaharlal Nehru University, New Delhi, 110067, India

    Ragothaman Yennamalli & Naidu Subbarao

  2. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, 4072, Australia

    Ragothaman Yennamalli, Thorsten Kampmann, Ross P. McGeary, Paul R. Young & Bostjan Kobe

  3. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia

    Paul R. Young & Bostjan Kobe

Authors
  1. Ragothaman Yennamalli
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  2. Naidu Subbarao
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  3. Thorsten Kampmann
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  4. Ross P. McGeary
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  5. Paul R. Young
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  6. Bostjan Kobe
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Correspondence to Bostjan Kobe.

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Yennamalli, R., Subbarao, N., Kampmann, T. et al. Identification of novel target sites and an inhibitor of the dengue virus E protein. J Comput Aided Mol Des 23, 333–341 (2009). https://doi.org/10.1007/s10822-009-9263-6

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  • DOI: https://doi.org/10.1007/s10822-009-9263-6

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