In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses

Kampmann, T., Yennamalli, R., Campbell, P., Stoermer, M. J., Fairlie, D. P., Kobe, B. and Young, P. R. (2009) In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. Antiviral Research, 84 3: 234-241. doi:10.1016/j.antiviral.2009.09.007


Author Kampmann, T.
Yennamalli, R.
Campbell, P.
Stoermer, M. J.
Fairlie, D. P.
Kobe, B.
Young, P. R.
Title In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses
Journal name Antiviral Research   Check publisher's open access policy
ISSN 0166-3542
Publication date 2009-12-01
Year available 2009
Sub-type Article (original research)
DOI 10.1016/j.antiviral.2009.09.007
Volume 84
Issue 3
Start page 234
End page 241
Total pages 8
Editor Earl R Kern
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Subject C1
920109 Infectious Diseases
060107 Enzymes
Abstract The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as it undergoes a low pH induced conformational change in the endosomal compartment of the host cell. This essential entry stage in the flavivirus life cycle provides an attractive target for the development of antiviral agents. We performed an in silico docking screen of the Maybridge chemical database within a previously described ligand binding pocket in the dengue E protein structure that is thought to play a key role in the conformational transitions that lead to membrane fusion. The biological activity of selected compounds identified from this screen revealed low micromolar antiviral potency against dengue virus for two of the compounds. Our results also provide the first evidence that compounds selected to bind to this ligand binding site on the flavivirus E protein abrogate fusion activity. Interestingly, one of these compounds also has antiviral activity against both WNV (kunjin strain) and YFV.
Keyword Dengue virus
Antiviral
Fusion inhibition
Flavivirus
Virtual screening
West Nile Virus
Borne Encephalitis-Virus
Membrane-Fusion
Monoclonal-Antibodies
Yellow-Fever Virus
Development Settings
Estimate Solubility
Crystal-Structure
Drug Discovery
E-Glycoprotein
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Sun, 20 Dec 2009, 10:05:21 EST