Origins of Resistance Conferred by the R292K Neuraminidase Mutation via Molecular Dynamics and Free Energy Calculations.

@article{Chachra2008OriginsOR,
  title={Origins of Resistance Conferred by the R292K Neuraminidase Mutation via Molecular Dynamics and Free Energy Calculations.},
  author={Ricky Chachra and Robert C. Rizzo},
  journal={Journal of chemical theory and computation},
  year={2008},
  volume={4 9},
  pages={
          1526-40
        }
}
  • Ricky Chachra, R. Rizzo
  • Published 12 August 2008
  • Chemistry, Biology
  • Journal of chemical theory and computation
Point mutations in the influenza virus enzyme neuraminidase (NA) have been reported that lead to dramatic loss of activity for known NA inhibitors including the FDA approved sialic acid mimics zanamivir and oseltamivir. A more complete understanding of the molecular basis for such resistance is a critical component toward development of improved next-generation drugs. In this study, we have used explicit solvent all-atom molecular dynamics simulations, free energy calculations (MM-GBSA), and… 
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Background Citations
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Methods Citations
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Results Citations
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For all NA subtypes, the electrostatic contributions are the major driving force for ligand binding and largely responsible for the binding differences between the wild-type and mutated NA proteins.
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An electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase is revealed, suggesting how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.
In silico study on multidrug resistance conferred by I223R/H275Y double mutant neuraminidase.
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A systematic in silico study to explore the structural basis underlying this multidrug resistance of the I223R/H275Y double mutant of neuraminidase (NA), finding the stronger resistance can be ascribed to the overall looser but locally more compact structure of the former.
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Investigation of the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine showed that single mutations at residue 184 of RT caused distortion of the orientation of lamivUDine in the active site.
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An atomic-level model of a T20-gp41 complex embedded in an explicit DOPC membrane was constructed, and molecular dynamics simulations, followed by binding energy analysis, were performed to delineate structural and energetic features that contribute to drug resistance.
Computational design of novel, high-affinity neuraminidase inhibitors for H5N1 avian influenza virus.
  • J. Park, W. Jo
  • Chemistry, Biology
    European journal of medicinal chemistry
  • 2010
Heating Dynamics Simulation of H274Y Mutant Neuraminidase-Inhibitors Complexes
The H274Y mutant neuraminidase, known as oseltamivir-resistant, can be inhibited by zanamivir and laninamivir. The inhibition of oseltamivir-resistant neuraminidase has been experimented in vivo and…
Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations
TLDR
Seven generalized Born molecular dynamics simulations of avian and human NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound suggest that entropic considerations cannot be neglected when comparing across the subtypes.
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