TCB Publications - Paper Request

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.

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.


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