Thesis (M.Sc.)--Chulalongkorn University, 2011

The influenza B virus causes epidemics of influenza in every 2-3 years serving high morbidity in humans. Oseltamivir, the neuraminidase (NA) inhibitor blocking the releasing of new viruses, is an effective agent against influenza B virus, however, the oseltamivir resistances conferring the E119G, R152K and D198N substitutions have been reported. In this study, molecular dynamics (MD) simulation was performed on the wild-type and the three NA mutants with oseltamivir bound. Based on three different of MD simulations, the wild-type system is the most stability which oseltamivir strongly binds through the five key residues E119, D151, R152, R292 and R371. The notable loss of hydrogen bond and the decrease in per-residue decomposition energy at the mutated residues G119 and K152 compared to those of the wild-type were found to be the primary source of high-level oseltamivir resistance in the E119G and R152K mutants, respectively. In addition, the larger cavities in the NA active site conferring with these two mutations at the –NH3+ and –NHAc side chains, respectively, were compensated by more accessibility of water molecules. In contrast to the low level oseltamvir resistance in D198N mutant, this strain only showed slightly decreased in hydrogen bonds. According to the MM/PBSA binding free energies, the order of oseltamivir efficiency is of wild-type > D198N > E119G > R152K in good agreement with the experimental IC50 values.