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

@article{An2009ANS,
  title={A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase.},
  author={Jianghong An and Davy C. W. Lee and Anna Hing-Yee Law and Cindy L. H. Yang and Leo L. M. Poon and Allan Sik Yin Lau and Steven J. M. Jones},
  journal={Journal of medicinal chemistry},
  year={2009},
  volume={52 9},
  pages={
          2667-72
        }
}
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… 
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References

SHOWING 1-10 OF 24 REFERENCES
The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design
TLDR
It may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs, according to X-ray crystallography, which shows that these two groups of neuraminidases are structurally distinct.
Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.
TLDR
The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described and the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid is revealed.
Remarkable loop flexibility in avian influenza N1 and its implications for antiviral drug design.
TLDR
It is shown that the 150-loop is able to open into significantly wider conformations than seen in the crystal structures, through explicitly solvated MD simulations of the apo and oseltamivir-bound forms of tetrameric N1.
Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble
TLDR
The synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS‐Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase provides further support for the feasibility of developing high‐affinity inhibitors capable of binding these regions.
Rational design of potent sialidase-based inhibitors of influenza virus replication
TLDR
Two potent inhibitors based on the crystal structure of influenza virus sialidase have been designed and provide an example of the power of rational, computer-assisted drug design, indicating significant progress in the development of a new therapeutic or prophylactic treatment for influenza infection.
p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1
TLDR
Findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway, which may provide insights into the pathogenesis of H 5N1 disease and rationales for the development of novel therapeutic strategies.
Avian flu: Isolation of drug-resistant H5N1 virus
TLDR
The isolation of an H5N1 virus from a Vietnamese girl that is resistant to the drug oseltamivir, which is an inhibitor of the viral enzyme neuraminidase and is currently used for protection against and treatment of influenza is reported.
Neuraminidase Is Important for the Initiation of Influenza Virus Infection in Human Airway Epithelium
TLDR
It is demonstrated that viral NA plays a role early in infection, and they provide further rationale for the prophylactic use of NA inhibitors.
Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages.
TLDR
The results showed that the delay in apoptosis onset in macrophages infected by H5N1/97 and its related precursor subtypes may be a means for the pathogens to have longer survival in the cells; this may contribute to the pathogenesis of H 5N1 disease in humans.
Pocketome via Comprehensive Identification and Classification of Ligand Binding Envelopes*
TLDR
A new computational algorithm for the accurate identification of ligand binding envelopes rather than surface binding sites is developed and the data base of the known and predicted binding pockets for the human proteome structures, the human pocketome, was collected and classified.
...
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