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Abstract. A Novel Small-Molecule Inhibitor of the Avian Influenza H5N1 Virus Determined through Computational Screening against the Neuraminidase.
A Novel Small-Molecule Inhibitor of the Avian Influenza H5N1 Virus Determined through Computational Screening against the Neuraminidase
Jianghong An?, Davy C. W. Lee?, Anna H.Y. Law?, Cindy L.H. Yang?, Leo L.M. Poon, Allan S.Y. Lau*? and Steven J.M. Jones*
?British Columbia Cancer Agency Genome Sciences Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 4S6, Canada, Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China
J. Med. Chem., Article ASAP
DOI: 10.1021/jm800455g
Publication Date (Web): April 15, 2009
Copyright ? 2009 American Chemical Society
?British Columbia Cancer Agency Genome Sciences Centre.,
?Immunology Research Laboratory, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China.,* To whom correspondence should be addressed. For A.S.Y.L.: phone, 852-28554269; fax, 852-28198142; E-mail, asylau@hkucc.hku.hk. For S.J.M.J.: phone, 604-877-6083; fax, 604-876-3561; E-mail, sjones@bcgsc.ca.
Abstract
Computational 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.
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<cite cite="http://pubs.acs.org/doi/abs/10.1021/jm800455g">A Novel Small-Molecule Inhibitor of the Avian Influenza H5N1 Virus Determined through Computational Screening against the Neuraminidase - Journal of Medicinal Chemistry (ACS Publications)</cite>
Jianghong An?, Davy C. W. Lee?, Anna H.Y. Law?, Cindy L.H. Yang?, Leo L.M. Poon, Allan S.Y. Lau*? and Steven J.M. Jones*
?British Columbia Cancer Agency Genome Sciences Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 4S6, Canada, Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China, and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China
J. Med. Chem., Article ASAP
DOI: 10.1021/jm800455g
Publication Date (Web): April 15, 2009
Copyright ? 2009 American Chemical Society
?British Columbia Cancer Agency Genome Sciences Centre.,
?Immunology Research Laboratory, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong.,Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China.,* To whom correspondence should be addressed. For A.S.Y.L.: phone, 852-28554269; fax, 852-28198142; E-mail, asylau@hkucc.hku.hk. For S.J.M.J.: phone, 604-877-6083; fax, 604-876-3561; E-mail, sjones@bcgsc.ca.
Abstract
Computational 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.
-