Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok, 10330, Thailand.
Amino Acids. 2009 Oct;37(4):725-32. doi: 10.1007/s00726-008-0201-z. Epub 2008 Nov 12.
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 -NH(3) (+) 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.
对突变奥司他韦-NA 复合物进行了分子动力学模拟，以提供有关流感病毒神经氨酸酶（NA）中 H274Y 突变导致奥司他韦耐药性的详细信息。与之前的提议相反，H274Y 突变并没有阻止 E276 和 R224 形成奥司他韦庞大基团的疏水口袋。相反，在该庞大基团的乙基部分周围区域的口袋的疏水性和大小的减少被发现是奥司他韦耐药性的来源。这些变化主要是由于亲水-COO（-）基团的 E276 向乙基部分的剧烈旋转引起的。此外，奥司他韦的-NH（3）（+）和-NHAc 基团的 N1 残基的氢键相互作用被一个水分子取代。奥司他韦与 NA 的计算结合亲和力从野生型的-14.6 kcal mol（-1）显著降低到突变型的-9.9 kcal mol（-1）。
