A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase.
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.
An
Jianghong
J
British Columbia Cancer Agency Genome Sciences Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 4S6, Canada.
Lee
Davy C W
DC
Law
Anna H Y
AH
Yang
Cindy L H
CL
Poon
Leo L M
LL
Lau
Allan S Y
AS
Jones
Steven J M
SJ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001717:Birds; D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology; D005585:Influenza in Birds / Q000821:virology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C540943:4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)propyl)amino)phenyl)-1-chloro-3-buten-2-one; D000998:Antiviral Agents; D011743:Pyrimidines; D054852:Small Molecule Libraries; D009439:Neuraminidase