Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation |
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Authors: | Malaisree Maturos Rungrotmongkol Thanyada Nunthaboot Nadtanet Aruksakunwong Ornjira Intharathep Pathumwadee Decha Panita Sompornpisut Pornthep Hannongbua Supot |
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Institution: | (1) Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, 10330, Thailand;(2) Department of Chemistry, Faculty of Science, Mahasarakham University, Mahasarakham, 44150, Thailand;(3) Department of Chemistry, Faculty of Science, Rangsit University, Pathumtani, 12000, Thailand; |
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Abstract: | Molecular dynamics simulations were carried out for the mutant oseltamivir-NA complex, to provide detailed information on
the oseltamivir-resistance resulting from the H274Y mutation in neuraminidase (NA) of avian influenza H5N1 viruses. In contrast
with a previous proposal, the H274Y mutation does not prevent E276 and R224 from forming the hydrophobic pocket for the oseltamivir
bulky group. Instead, reduction of the hydrophobicity and size of pocket in the area around an ethyl moiety at this bulky
group were found to be the source of the oseltamivir-resistance. These changes were primarily due to the dramatic rotation
of the hydrophilic –COO− group of E276 toward the ethyl moiety. In addition, hydrogen-bonding interactions with N1 residues at the -NH3
+ and -NHAc groups of oseltamivir were replaced by a water molecule. The calculated binding affinity of oseltamivir to NA was
significantly reduced from −14.6 kcal mol−1 in the wild-type to −9.9 kcal mol−1 in the mutant-type. |
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