Molecular Dynamics Studies Of The Effects Of Neuraminidase Mutation On Oseltamivir Resistance
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Date
2015-10
Authors
YUSUF, MUHAMMAD
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Abstract
The increased number of reports on oseltamivir (OTV) resistant strains of
influenza virus (e.g. H274Y mutation on its neuraminidase, NA) has created some
causes for concern. Many studies have been conducted to uncover the mechanism of
OTV resistances in H274Y NA. However, most of the reported studies on H274Y were
only focused on drug-bound-system, while direct effects of the mutation towards NA
itself, prior to drug binding, remains unclear. Therefore, molecular dynamics of NA in
apo-form, followed by principal component analysis and interaction energy
calculation, were performed to investigate the structural changes of NA binding site,
as a result of H274Y mutation. The disruption of NA binding site due to H274Y,
initiated by the repulsive effect of Y274 on 250-loop - which in turn altered the
hydrogen bond network around residue 274, was observed. The rotated W295 side
chain has caused the upwards movement of 340-loop. Consequently, sliding-box
docking results suggested that the binding pathway of OTV was compromised due to
this binding site disruption. This study also highlighted the importance of functional
group at position C6 of sialic acid mimicry. Moreover, two possible keys to explain
the differences of H274Y effects in N1- and N2- subtypes, were proposed: residue 245,
and the residue which formed π-interaction with W296. Similar approaches were
applied to explain the effects of N294S and R292K mutations in N1- and N9- subtypes,
respectively. The disruption of calcium binding in N294S mutant was observed. While
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the changes of NA’s core structure occurred in R292K mutant. For the first time, the
mechanism of OTV resistance was extensively studied from the state of NA prior to
drug binding. It is hoped that these results could improve the understanding of OTV
resistances and shed some light on the design of novel anti-influenza drug.
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Molecular Dynamics Studies Of The Effects Of , Neuraminidase Mutation On Oseltamivir Resistance