Correlation Analyses on Binding Affinity of Sialic Acid Analogues and Anti-Influenza Drugs with Human Neuraminidase Using ab Initio MO Calculations on Their Complex Structures - LERE-QSAR Analysis (IV)
Correlation Analyses on Binding Affinity of Sialic Acid Analogues and Anti-Influenza Drugs with Human Neuraminidase Using ab Initio MO Calculations on Their Complex Structures - LERE-QSAR Analysis (IV)
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DOI：
10.1021/ci2002395
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发表时间：
2011-09
影响因子：
5.6
通讯作者：
Seiji Hitaoka;Hiroshi Matoba;M. Harada;Tatsusada Yoshida;D. Tsuji;T. Hirokawa;K. Itoh;H. Chuman
中科院分区：
文献类型：
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作者：
Seiji Hitaoka;Hiroshi Matoba;M. Harada;Tatsusada Yoshida;D. Tsuji;T. Hirokawa;K. Itoh;H. Chuman
我们对人神经氨酸酶-2(HNEU2)与唾液酸类似物(包括抗流感药物扎那米韦(瑞沙)和奥司他韦(达菲))的络合物进行了全从头算片段分子轨道(FMO)计算，以考察观察到的对hNEU2的抑制活性在原子和电子水平上的变化。我们最近提出了LERE(代表能量项的线性表示)-QSAR(定量结构-活性关系)程序。LEE-QSAR定量分析表明，络合物的形成是由hNEU2与唾液酸类似物的氢键和静电相互作用驱动的。扎那米韦最强的抑制活性归因于扎那米韦中带正电荷的胍基与hNEU2中带负电荷的氨基酸残基之间的强烈静电相互作用。在我们确认唾液酸类似物之间观察到的抑制活性的变化可以很好地用Lere-QSAR方程重现性之后，我们检验了奥司他韦对hNEU2和甲型流感病毒神经氨酸酶-1(N1-NA)抑制效力显著差异的原因。在hNEU2和N1-NA中，与奥司他韦中带正电的氨基密切接触的几个氨基酸残基是不同的。FMO-IFIE(片段间相互作用能)分析表明，氨基酸残基的不同导致奥司他韦与hNEU2和N1-NA的总相互作用能有很大差异。目前的结果将有助于开发具有高选择性且没有不良副作用风险的新型抗流感药物。
We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.