Ariela Vergara-Jaque, Horacio Poblete, Eric Lee, Klaus Schulten, Fernando
González-Nilo, and Christophe Chipot.
Molecular basis of drug resistance in A/H1N1 virus.
Journal of Chemical Information and Modeling, 52:2650-2656,
2012.
(PMC: DNA/NIH)
VERG2012
New mutants of human influenza virus (A/H1N1) exhibit resistance to antiviral drugs. The
mechanism whereby they develop insensitivity to these medications is, however, not yet
completely understood. A crystallographic structure of A/H1N1 neuraminidase has been
published recently. Using molecular dynamic simulations, it is now possible to characterize
at the atomic level the mechanism that underlies the loss of binding affinity of the drugs.
In this study, free-energy perturbation was used to evaluate the relative binding free
energies of Tamiflu and Relenza with H274Y, N294S and Y252H neuraminidase mutants.
Our results demonstrate a remarkable correlation between theoretical and experimental
data, which quantitatively confirms that the mutants are resistant to Tamiflu, but are still
strongly inhibited by Relenza. The simulations further reveal the key interactions that
govern the affinity of the two drugs for each mutant. This information is envisioned to
prove useful for the design of novel neuraminidase inhibitors and for the characterization
of new potential mutants.
Download Full Text
The manuscripts available on our site are provided for your personal
use only and may not be retransmitted or redistributed without written
permissions from the paper's publisher and author. You may not upload any
of this site's material to any public server, on-line service, network, or
bulletin board without prior written permission from the publisher and
author. You may not make copies for any commercial purpose. Reproduction
or storage of materials retrieved from this web site is subject to the
U.S. Copyright Act of 1976, Title 17 U.S.C.
