Article: A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase

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TitleA novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase
AuthorsAn, J2
Lee, DCW1
Law, AHY1
Yang, CLH1
Poon, LLM1
Lau, ASY1
Jones, SJM2
Issue Date2009
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/jmc
CitationJournal Of Medicinal Chemistry, 2009, v. 52 n. 9, p. 2667-2672 [How to Cite?]
DOI: http://dx.doi.org/10.1021/jm800455g
AbstractComputational molecular docking provides an efficient and innovative approach to examine small molecule and protein interactions. We have utilized this method to identify potential inhibitors of the H5N1 neuraminidase protein. Of the 20 compounds tested, 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)- propyl)amino)phenyl)-1-chloro-3-buten-2-one (1) (NSC89853) demonstrated the ability to inhibit viral replication at a level comparable to the known neuraminidase inhibitor oseltamivir. Compound 1 demonstrated efficacy across a number of cell-lines assays and in both the H1N1 and H5N1 viruses. The predicted binding of 1 to the known H5N1 neuraminidase structure indicates a binding interface largely nonoverlapping with that of oseltamivir or another neuraminidase inhibitor zanamivir. These results indicate that 1 or similar molecules would remain effective in the presence of virus mutations conferring resistance to either oseltamivir or zanamivir and also vice versa. © 2009 American Chemical Society.
ISSN0022-2623
2011 Impact Factor: 5.248
2011 SCImago Journal Rankings: 0.451
DOIhttp://dx.doi.org/10.1021/jm800455g
ISI Accession Number IDWOS:000265911800004
Funding AgencyGrant Number
Michael Smith Foundation for Health Research
Area of Excellence Scheme of the University Grants CommitteeAoE/M-12/06
Funding Information:

We are grateful to the Developmental Therapeutics Program, National Cancer Institute, USA, for providing the chemical compounds in this project. S.J.M.J. is a scholar of the Michael Smith Foundation for Health Research. The project is funded in part by the Area of Excellence Scheme of the University Grants Committee (Grant AoE/M-12/06) of Hong Kong and Prof. Francis SK Lau Research Fund awarded to Dr. A. Lau.

ReferencesReferences in Scopus
GrantsControl of Pandemic and Inter-pandemic Influenza
DC Field
Value
dc.contributor.authorAn, J
dc.contributor.authorLee, DCW
dc.contributor.authorLaw, AHY
dc.contributor.authorYang, CLH
dc.contributor.authorPoon, LLM
dc.contributor.authorLau, ASY
dc.contributor.authorJones, SJM
dc.date.accessioned2010-05-31T03:49:42Z
dc.date.available2010-05-31T03:49:42Z
dc.date.issued2009
dc.description.abstractComputational molecular docking provides an efficient and innovative approach to examine small molecule and protein interactions. We have utilized this method to identify potential inhibitors of the H5N1 neuraminidase protein. Of the 20 compounds tested, 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)- propyl)amino)phenyl)-1-chloro-3-buten-2-one (1) (NSC89853) demonstrated the ability to inhibit viral replication at a level comparable to the known neuraminidase inhibitor oseltamivir. Compound 1 demonstrated efficacy across a number of cell-lines assays and in both the H1N1 and H5N1 viruses. The predicted binding of 1 to the known H5N1 neuraminidase structure indicates a binding interface largely nonoverlapping with that of oseltamivir or another neuraminidase inhibitor zanamivir. These results indicate that 1 or similar molecules would remain effective in the presence of virus mutations conferring resistance to either oseltamivir or zanamivir and also vice versa. © 2009 American Chemical Society.
dc.description.grantControl of Pandemic and Inter-pandemic Influenza
dc.description.grantcode97655
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationJournal Of Medicinal Chemistry, 2009, v. 52 n. 9, p. 2667-2672 [How to Cite?]
DOI: http://dx.doi.org/10.1021/jm800455g
dc.identifier.citeulike4373289
dc.identifier.doihttp://dx.doi.org/10.1021/jm800455g
dc.identifier.epage2672
dc.identifier.hkuros159177
dc.identifier.isiWOS:000265911800004
Funding AgencyGrant Number
Michael Smith Foundation for Health Research
Area of Excellence Scheme of the University Grants CommitteeAoE/M-12/06
Funding Information:

We are grateful to the Developmental Therapeutics Program, National Cancer Institute, USA, for providing the chemical compounds in this project. S.J.M.J. is a scholar of the Michael Smith Foundation for Health Research. The project is funded in part by the Area of Excellence Scheme of the University Grants Committee (Grant AoE/M-12/06) of Hong Kong and Prof. Francis SK Lau Research Fund awarded to Dr. A. Lau.

dc.identifier.issn0022-2623
2011 Impact Factor: 5.248
2011 SCImago Journal Rankings: 0.451
dc.identifier.issue9
dc.identifier.openurl
dc.identifier.pmid19419201
dc.identifier.scopuseid_2-s2.0-65649103683
dc.identifier.spage2667
dc.identifier.urihttp://hdl.handle.net/10722/59418
dc.identifier.volume52
dc.languageeng
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/jmc
dc.publisher.placeUnited States
dc.relation.ispartofJournal of Medicinal Chemistry
dc.relation.referencesReferences in Scopus
dc.titleA novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. British Columbia Cancer Agency