Binding mode prediction and inhibitor design of anti-influenza virus diketo acids targeting metalloenzyme RNA polymerase by molecular docking
Binding mode prediction and inhibitor design of anti-influenza virus diketo acids targeting metalloenzyme RNA polymerase by molecular docking
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DOI：
10.6026/97320630006221
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发表时间：
2011-01-01
期刊：
影响因子：
1.9
通讯作者：
Fujii, Satoshi
中科院分区：
文献类型：
--
作者：
Ishikawa, Yoshinobu;Fujii, Satoshi
流感是每年的季节性威胁和死亡的主要原因，特别是在儿童和老年人中。虽然神经氨酸酶抑制剂和M2蛋白阻断剂用于用药，但耐药性已逐渐出现。因此，迫切需要开发靶向病毒的不同组成蛋白的有效抗流感药物。基于此，我们进行了分子对接，预测了抗流感病毒二酮酸抑制剂在流感病毒金属酶RNA聚合酶PA（N）亚基活性位点的结合模式。计算结果表明，双阴离子形式的二酮酸应作为双核配体螯合双核锰中心，并将其螯合，疏水取代基较大的二酮酸衍生物应更紧密地封闭活性中心的疏水空腔.这些假设可以充分解释这些化合物对酶的抑制作用。此外，我们还从热力学角度出发，通过对二酮酸类缓蚀剂的先导优化，设计出了潜在的缓蚀剂。分子对接结果表明，新设计的二酮酸衍生物对金属酶RNA聚合酶的抑制作用可能比先导化合物更强。
Influenza is a yearly seasonal threat and major cause of mortality, particularly in children and the elderly. Although neuraminidase inhibitors and M2 protein blockers are used for medication, drug resistance has gradually emerged. Thus, the development of effective anti-influenza drugs targeting different constituent proteins of the virus is urgently desired. In this light, we carried out molecular docking to predict the binding modes of anti-influenza diketo acid inhibitors in the active site of the PA(N) subunit of the metalloenzyme RNA polymerase of influenza virus. The calculations suggested that the dianionic forms of the diketo acids should chelate the dinuclear manganese center as dinucleating ligands and sequester it. They also indicated that the diketo acid derivatives with larger hydrophobic substituents should block a hydrophobic cavity in the active site more tightly. These assumptions could adequately explain the enzyme inhibition by these compounds. Furthermore, we designed potential inhibitors by lead optimization of a diketo acid inhibitor from the thermodynamic points of view. Molecular docking results showed that the newly designed diketo acid derivatives might inhibit the metalloenzyme RNA polymerase more strongly than the lead inhibitor.