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J Chem Inf Model. 2009 Dec;49(12):2735-41. doi: 10.1021/ci900348n.

Infiltration of water molecules into the oseltamivir-binding site of H274Y neuraminidase mutant causes resistance to oseltamivir.

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Department of Materials Science and Engineering, Seoul National University, Seoul 151-742, Korea.


The oseltamivir-resistant neuraminidase mutant, His274Tyr (H274Y), has recently been identified in humans. The objective of our present research is to elucidate the origin of resistance of the H274Y mutation to oseltamivir (OTV) at the molecular level via molecular dynamics simulation. For this purpose, the binding free energies of OTV with the wild-type N1 subtype and with the H274Y mutant were calculated using the linear interaction energy method. The nonbonded interaction energies between OTV and active-site residues were also calculated to investigate the contribution of nonbonded interactions to the total binding free energy. Our molecular dynamics trajectories revealed marked differences between these two structures, particularly in the binding modes of OTV. Contrary to the existing prediction, a salt bridge between Glu276 and Arg224 was retained in the OTV-bound H274Y mutant throughout the simulation. This study reveals that water molecules can infiltrate into the binding site of the H274Y mutant, suggesting that the origin of H274Y resistance to OTV is caused by penetration of water molecules into the binding site and not by disruption of the Glu276-Arg224 salt bridge. These results will be useful for the rational design of neuraminidase inhibitors having high potency against known drug-resistant H5N1 mutants.

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