source: via Lancet http://www.thelancet.com/H1N1-flu
Extracts from the report follow.
The recent outbreak of the novel strain of influenza A (H1N1) virus has raised a global concern of the
future risk of a pandemic. To understand at the molecular level how this new H1N1 virus can be inhibited
by the current anti-influenza drugs and which of these drugs it is likely to already be resistant to, homology
modeling and MD simulations have been applied on the H1N1 neuraminidase complexed with oseltamivir,
and the M2-channel with adamantanes bound. The H1N1 virus was predicted to be susceptible
to oseltamivir, with all important interactions with the binding residues being well conserved. In contrast,
adamantanes are not predicted to be able to inhibit the M2 function and have completely lost their
binding with the M2 residues. This is mainly due to the fact that the M2 transmembrane of the new H1N1
strain contains the S31N mutation which is known to confer resistance to adamantanes.
The new A (H1N1) virus contains the combination of gene segments
of swine, avian and human influenza viruses. Based on genetic
characterization, the hemagglutinin (HA) gene is similar to
that of the swine influenza virus currently circulating amongst
USA pigs, whilst the neuraminidase (NA) and matrix protein (M)
genes are similar to those of swine influenza viruses isolated from
Due to antigenic differences amongst influenza A strains, the
current seasonal influenza vaccines cannot provide protection
against this new strain of A (H1N1) influenza virus. Up to date,
there are two classes of anti-influenza agents: (i) NA inhibitors,
oseltamivir and zanamivir, protecting the release and spread of
progeny virions; (ii) adamantane derivatives, amantadine and
rimantadine, preventing the proton transfer in the M2 ion-channel
. The A (H1N1) viruses isolated from patients in USA and Mexico
are sensitive to NA inhibitors but show resistance to adamantane
To gain the fundamental knowledge on the structure and the
drug–target interactions of the new strain of influenza A (H1N1)
virus, homology modeling and molecular dynamics (MD) simulations
were carried out on the three inhibitor–enzyme complexes:
OTV-NA, AMT-M2 and RMT-M2.
Results and discussion
All calculations are modeled and discussed in comparison to our
previous studies on the avian H5N1 influenza NA (N1/04H5N1) [6–
8,14] and M2-channel (M2/04H5N1) [9,10]. Relative to N1/
04H5N1, all residues in the N1/09H1N1 binding pocket are conserved
except for one, the tyrosine (Y374) being replaced by asparagine
(N374) (Fig. 1A). This is not the case for the M2-channel in
which amongst the 19 key residues three were changed, that is
the I28 and N31 at the extracellular site and T43 close to the gating
tryptophan (W41) of M2/09H1N1, were changed from V28, S31
and L43 of the M2/04H5N1, respectively (Fig. 1B).
Efficiency of oseltamivir against influenza A (H1N1) neuraminidase
To estimate the binding free energies (DGbind) of oseltamivir
and its four sidechains against the 2009 A (H1N1) influenza NA...
In the present study, homology modeling and MD simulations
were applied on the commercially available drugs bound to the
NA and M2-channel of the new influenza A (H1N1) virus. Based
on the MD/LIE method, the predicted binding affinity of oseltamivir
towards the new A (H1N1) influenza isolate was considerably
higher than the avian H5N1 strain. Except for the absence of a
weak H-bond with residue 347, all interactions of OTV-N1/
09H1N1 complex were considerably conserved. Interestingly, oseltamivir
was well oriented in the binding pocket and its –COO
group interacted strongly with the arginine triad, similar to that
found in the crystal structure of N9.
Overall, the simulated results have clearly
explained at a molecular level how anti-influenza drugs can either
potently inhibit (oseltamivir) or not (amantadine and rimantadine)
the new A (H1N1) influenza virus.
The calculated binding affinities
lead us to conclude that the new A (H1N1) influenza virus is more
sensitive to oseltamivir than the avian H5N1 influenza.