tetano
Editor, Senior Moderator
J Comput Aided Mol Des. 2019 Nov 26. doi: 10.1007/s10822-019-00251-7. [Epub ahead of print] [h=1]Source of oseltamivir resistance due to single E119D and double E119D/H274Y mutations in pdm09H1N1 influenza neuraminidase.[/h]
Hanpaibool C[SUP]1[/SUP], Leelawiwat M[SUP]1[/SUP], Takahashi K[SUP]1,[/SUP][SUP]2[/SUP], Rungrotmongkol T[SUP]3,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h] 1 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. 2 Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 10617, Taiwan. 3 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com. 4 Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com.
[h=3]Abstract[/h] Influenza epidemics are responsible for an average of 3-5 millions of severe cases and up to 500,000 deaths around the world. One of flu pandemic types is influenza A(H1N1)pdm09 virus (pdm09H1N1). Oseltamivir is the antiviral drug used to treat influenza targeting at neuraminidase (NA) located on the viral surface. Influenza virus undergoes high mutation rates and leads to drug resistance, and thus the development of more efficient drugs is required. In the present study, all-atom molecular dynamics simulations were applied to understand the oseltamivir resistance caused by the single E119D and double E119D/H274Y mutations on NA. The obtained results in terms of binding free energy and intermolecular interactions in the ligand-protein interface showed that the oseltamivir could not be well accommodated in the binding pocket of both NA mutants and the 150-loop moves out from oseltamivir as an "open" state. A greater number of water molecules accessible to the binding pocket could disrupt the oseltamivir binding with NA target as seen be high mobility of oseltamivir at the active site. Additionally, our finding could guide to the design and development of novel NA inhibitor drugs.
[h=4]KEYWORDS:[/h] E119D/H274Y mutant; H1N1; Molecular dynamics; Neuraminidase; Oseltamivir resistance
PMID: 31773463 DOI: 10.1007/s10822-019-00251-7
Hanpaibool C[SUP]1[/SUP], Leelawiwat M[SUP]1[/SUP], Takahashi K[SUP]1,[/SUP][SUP]2[/SUP], Rungrotmongkol T[SUP]3,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h] 1 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. 2 Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 10617, Taiwan. 3 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com. 4 Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com.
[h=3]Abstract[/h] Influenza epidemics are responsible for an average of 3-5 millions of severe cases and up to 500,000 deaths around the world. One of flu pandemic types is influenza A(H1N1)pdm09 virus (pdm09H1N1). Oseltamivir is the antiviral drug used to treat influenza targeting at neuraminidase (NA) located on the viral surface. Influenza virus undergoes high mutation rates and leads to drug resistance, and thus the development of more efficient drugs is required. In the present study, all-atom molecular dynamics simulations were applied to understand the oseltamivir resistance caused by the single E119D and double E119D/H274Y mutations on NA. The obtained results in terms of binding free energy and intermolecular interactions in the ligand-protein interface showed that the oseltamivir could not be well accommodated in the binding pocket of both NA mutants and the 150-loop moves out from oseltamivir as an "open" state. A greater number of water molecules accessible to the binding pocket could disrupt the oseltamivir binding with NA target as seen be high mobility of oseltamivir at the active site. Additionally, our finding could guide to the design and development of novel NA inhibitor drugs.
[h=4]KEYWORDS:[/h] E119D/H274Y mutant; H1N1; Molecular dynamics; Neuraminidase; Oseltamivir resistance
PMID: 31773463 DOI: 10.1007/s10822-019-00251-7