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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?
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How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?

机译：oseltamivir的每个取代基官能团如何失去对强毒H5N1流感病毒突变体的活性？

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摘要

To reveal the source of oseltamivir-resistance in influenza (A/H5N1) mutants, the drug-target interactions at each functional group were investigated using MD/LIE simulations. Oseltamivir in the H274Y mutation primarily loses the electrostatic and the vdW interaction energies at the -NH(3)(+) and -OCHEt(2) moieties corresponding to the weakened hydrogen-bonds and changed distances to N1 residues. Differentially, the N294S mutation showed small changes of binding energies and intermolecular interactions. Interestingly, the presence of different conformations of E276 positioned between the -OCHEt(2) group and the mutated residue is likely to play an important role in oseltamivir-resistant identification. In the H274Y mutant, it moves towards the -OCHEt(2) group leading to a reduction in hydrophobicity and pocket size, whilst in the N294S mutant it acts as the hydrogen network center bridging with R224 and the mutated residue S294. The molecular details have answered a question of how the H274Y and N294S mutations confer the high- and medium-level of oseltamivir-resistance to H5N1.
机译：为了揭示流感病毒（A / H5N1）突变体中耐奥司他韦的来源，使用MD / LIE模拟研究了每个功能组的药物-靶标相互作用。在H274Y突变中的Oseltamivir主要失去了在-NH（3）（+）和-OCHEt（2）部分的静电和vdW相互作用能，这对应于弱的氢键和与N1残基的距离改变。不同的是，N294S突变显示出结合能和分子间相互作用的微小变化。有趣的是，位于-OCHEt（2）组和突变残基之间的E276不同构象的存在可能在耐奥司他韦的鉴定中起重要作用。在H274Y突变体中，它移向-OCHEt（2）基团，导致疏水性和口袋尺寸减小，而在N294S突变体中，它充当氢网络中心，与R224和突变残基S294桥接。分子细节已经回答了一个问题，即H274Y和N294S突变如何赋予H5N1高和中等水平的奥司他韦耐药性。

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