Oseltamivir, which targets the neuraminidase of Influenza A virus (IAV), has been reported to develop resistance. Here, we performed a computational study on the binding modes of oseltamivir in the wild-type (WT) and popular mutants of IAV neuraminidase (E119A, E119D, E119G, H274Y, I117T, I117V, I117V-E119A, K150N, N294S, R292K, V116A, and Y252H). The Arg118, Glu119, Asp151, Arg152, Glu276, Arg292, and Arg371 were identified as as crucial interacting residues with the drug. The energy decomposition analysis (EDA) showed that with few exceptions, the dispersion interaction is the dominant interaction, followed by the charge-transfer and polarization interactions. The affinities for oseltamivir were greatly reduced in all mutant systems, particularly in R292K and Y252H. The present study may be substantial in the design of new oseltamivir analogs with better affinities to overcome the present drug resistance.
Key words: influenza A virus; Oseltamivir resistance; neuraminidase; MD simulation; protein mutation
|
