Designing Inhibitors of M2 Proton Channel against H1N1 Swine Influenza Virus

@article{Du2010DesigningIO,
  title={Designing Inhibitors of M2 Proton Channel against H1N1 Swine Influenza Virus},
  author={Q. Du and Ri-Bo Huang and Shu-Qing Wang and K. Chou},
  journal={PLoS ONE},
  year={2010},
  volume={5}
}
Background M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591–595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus. Methodology Docking… Expand
IN SILICO DESIGN OF THE M2 PROTON CHANNEL INHIBITORS OF H1N1 VIRUS
M2 proton channel of H1N1 Influenza A virus is the target protein anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity becauseExpand
Molecular dynamics analysis of potent inhibitors of M2 proton channel against H1N1 swine influenza virus
The recent H1N1 (swine) influenza pandemic highlighted the urgent need of having effective anti‐viral strategies. In addition to neuraminidase inhibitors, there is another class of anti-viral drugExpand
Structural and energetic analysis of drug inhibition of the influenza A M2 proton channel.
TLDR
It is shown that structural biology experiments and molecular modeling have led to the successful design of novel drugs targeting mutant M2 channels, and these recent studies on drug resistance and drug design of the mutant channels, focusing on the structures and energetics. Expand
Key features for designing M2 proton channel anti swine flu inhibitors
TLDR
The MD simulation has identified and conformationally validated five potential M2 inhibitors from traditional Chinese medicine using a freely accessible TCM database and provides insights to next generation of drug design. Expand
Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling
TLDR
The two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus. Expand
Binding Drugs on Two Position of M2 Proton Channel and Its Mutants
M2 protein plays as an proton channel in influenza virus, and many candidates were proposed to inhibit its activity. Three new inhibitors were proposed recently by Du Q-S, et al. (2010), and theirExpand
Random Mutagenesis Analysis of the Influenza A M2 Proton Channel Reveals Novel Resistance Mutants.
TLDR
A newly developed proton conduction assay is combined with an established method for selection and screening, both Escherichia coli-based, to enable the study of M2 function and inhibition. Expand
Identification of Novel Compounds against an R294K Substitution of Influenza A (H7N9) Virus Using Ensemble Based Drug Virtual Screening
TLDR
Virtual screening targeting the Neuraminidase (NA) protein against natural compounds of traditional Chinese medicine database (TCM) and ZINC natural products to identify novel inhibitors combat resistant strains of influenza virus H7N9 is performed. Expand
Coexistence of two adamantane binding sites in the influenza A M2 ion channel
TLDR
SPR results are in excellent agreement with the most recent solid-state NMR study of amantadine-bound M2 in lipid bilayers and provide independent support that the ion channel pore-binding site is responsible for the pharmacological activity elicited by the adamantane drugs. Expand
Recent progress and challenges in the computer-aided design of inhibitors for influenza A M2 channel proteins
TLDR
This review provides a summary of recent progress in drug discovery toward the development of therapeutic agents targeting M2 channel proteins and encourages the design of new and improved drugs against influenza A virus. Expand
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References

SHOWING 1-10 OF 43 REFERENCES
Mechanism of drug inhibition and drug resistance of influenza A M2 channel
TLDR
Structural and functional experiments on the mechanism of drug inhibition and resistance of the S31N drug-resistant mutant of M2, a mutant of the highly pathogenic avian influenza subtype H5N1, show that replacing Ser-31 with Asn has little effect on the structure of the channel pore, but dramatically reduces drug binding to the allosteric site. Expand
Energetic analysis of the two controversial drug binding sites of the M2 proton channel in influenza A virus.
TLDR
In-depth computational analysis of the structure of the M2 proton channel of influenza A finds that the conclusions drawn from various aspects, such as energetics, the channel-gating dynamic process, the pK(a) shift and its impact on the channel, and the consistency with the previous functional studies, are all in favour to the allosteric mechanism revealed by the NMR structure. Expand
Investigation into adamantane-based M2 inhibitors with FB-QSAR.
TLDR
A benchmark dataset has been constructed that contains 34 newly-developed adamantane-based M2 inhibitors and covers considerable structural diversities and wide range of bioactivities, and an in-depth analysis was performed with the newly developed fragment-based quantitative structure-activity relationship (FB-QSAR) algorithm. Expand
The chemical and dynamical influence of the anti-viral drug amantadine on the M2 proton channel transmembrane domain.
TLDR
The nuclear spin relaxation data and polarization inversion spin exchange at the magic angle spectra show that both the polypeptide backbone and His(37) side chain are more constrained in the presence of amantadine. Expand
Structure and mechanism of the M2 proton channel of influenza A virus
TLDR
The structure of the tetrameric M2 channel in complex with rimantadine, determined by NMR is presented and predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix–helix packing, thus facilitating channel opening. Expand
Influenza A virus M2 ion channel protein: a structure-function analysis
TLDR
A structure-function analysis of the influenza A virus M2 ion channel protein was performed, and the data indicate that changing residues on this face of the putative alpha helix of the M2 transmembrane (TM) domain alters properties of theM2 ions channel. Expand
An in-depth analysis of the biological functional studies based on the NMR M2 channel structure of influenza A virus.
TLDR
An in-depth analysis was performed for these functional studies, particularly for the mutations D44N, D44A and N44D on position 44, and the mutations on positions 27-38, to provide compelling evidences to further validate the NMR structure and very useful clues for dealing with the drug-resistance problems and developing new effective drugs against H5N1 avian influenza virus. Expand
Structural studies of the resistance of influenza virus neuramindase to inhibitors.
TLDR
The sensitivity of neuraminidase variants E119G and R292K to BCX-1812 has been measured and found in both cases to be intermediate between those of zanamivir and oseltamivIR. Expand
Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.
TLDR
Phylogenetic analysis of the HA and M genes indicates that the acquisition of resistance in A(H1N1) viruses can be linked to a specific genetic group and was not a result of reassortment between A (H3N2) and A( H1N 1) viruses. Expand
Roles of the histidine and tryptophan side chains in the M2 proton channel from influenza A virus
TLDR
The M2 protein form influenza A virus forms a tetrameric ion channel, which enables proton passage across biological membranes when the N‐terminal side is acidified, and current knowledge about the structures and interactions of His37 and Trp41 suggests a model for the M2 ion channel. Expand
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