tetano
Editor, Senior Moderator
J Biomol Struct Dyn. 2020 May 14:1-17. doi: 10.1080/07391102.2020.1765872. [Epub ahead of print]
Novel oseltamivir-resistant mutations distant from the active site of influenza B neuraminidase.
Kato Y[SUP]1,[/SUP][SUP]2[/SUP], Takahashi K[SUP]3[/SUP], Ito F[SUP]2[/SUP], Suzuki S[SUP]2[/SUP], Fukui K[SUP]1[/SUP], Mimaki M[SUP]3[/SUP], Suzuki K[SUP]2[/SUP].
Author information
Abstract
We performed a neuraminidase sequence analysis of thirty-two pediatric patients with influenza B who visited Teikyo University Hospital from January 2016 to March 2017, and found oseltamivir-resistant samples belonging to the Yamagata and Victoria lineages. Comparison with the neuraminidase sequence of oseltamivir-susceptible B/Brisbane/60/2008 revealed 5 common amino acid substitutions in many of these samples. According to the binding free energy calculation, the N340D and E358K substitutions reduced the affinity of oseltamivir to neuraminidase. Unexpectedly, these substitutions were located distant from the oseltamivir-binding site in neuraminidase. According to the molecular dynamics simulations, the N340D substitution rearranged complicated hydrogen bond networks in an extensive surface region of neuraminidase. The E358K substitution extensively altered the electrostatic potential map of the overall neuraminidase structure. Through these novel mechanisms, the N340D and E358K substitutions indirectly influenced the affinity reduction. These results may be useful for designing drugs for the treatment of oseltamivir-resistant virus infections.
KEYWORDS:
Influenza B; binding free energy; drug resistance; electrostatic potential; hydrogen bond; molecular dynamics; neuraminidase inhibitor; oseltamivir; virus
PMID:32406800DOI:10.1080/07391102.2020.1765872
Novel oseltamivir-resistant mutations distant from the active site of influenza B neuraminidase.
Kato Y[SUP]1,[/SUP][SUP]2[/SUP], Takahashi K[SUP]3[/SUP], Ito F[SUP]2[/SUP], Suzuki S[SUP]2[/SUP], Fukui K[SUP]1[/SUP], Mimaki M[SUP]3[/SUP], Suzuki K[SUP]2[/SUP].
Author information
Abstract
We performed a neuraminidase sequence analysis of thirty-two pediatric patients with influenza B who visited Teikyo University Hospital from January 2016 to March 2017, and found oseltamivir-resistant samples belonging to the Yamagata and Victoria lineages. Comparison with the neuraminidase sequence of oseltamivir-susceptible B/Brisbane/60/2008 revealed 5 common amino acid substitutions in many of these samples. According to the binding free energy calculation, the N340D and E358K substitutions reduced the affinity of oseltamivir to neuraminidase. Unexpectedly, these substitutions were located distant from the oseltamivir-binding site in neuraminidase. According to the molecular dynamics simulations, the N340D substitution rearranged complicated hydrogen bond networks in an extensive surface region of neuraminidase. The E358K substitution extensively altered the electrostatic potential map of the overall neuraminidase structure. Through these novel mechanisms, the N340D and E358K substitutions indirectly influenced the affinity reduction. These results may be useful for designing drugs for the treatment of oseltamivir-resistant virus infections.
KEYWORDS:
Influenza B; binding free energy; drug resistance; electrostatic potential; hydrogen bond; molecular dynamics; neuraminidase inhibitor; oseltamivir; virus
PMID:32406800DOI:10.1080/07391102.2020.1765872