Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Bioorg Med Chem. 2010 Jun 1;18(11):4074-84. doi: 10.1016/j.bmc.2010.04.010. Epub 2010 Apr 8.
Unlike the group-2 neuraminidase, the group-1 neuraminidase of influenza virus possesses a flexible loop (the 150-loop) and a cavity (the 150-cavity) adjacent to the active site, and renders a conformational change from the 'open' form to the 'closed' form on binding with substrate (sialo-glycoprotein) or inhibitor (e.g., zanamivir). Zanamivir derivative 8a having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidino group is designed as a possible inhibitor on the basis of computer docking to the open form of N1 subtype neuraminidase. Indeed, compound 8a exhibits strong neuraminidase inhibition and good anti-influenza activity against H1N1 virus with IC(50)=2.15microM and EC(50)=0.77microM, respectively. This study may provide a clue to future design of better group-1 neuraminidase inhibitors.
与神经氨酸酶 2 组不同，流感病毒的神经氨酸酶 1 组具有一个柔性环（150 环）和一个邻近活性部位的腔（150 腔），并在与底物（唾液酸糖蛋白）或抑制剂（例如扎那米韦）结合时发生从“开”构象到“闭”构象的构象变化。具有胍基内部 N 位上扩展的（哌嗪羰基）丙基取代基的扎那米韦衍生物 8a 是基于计算机对接 N1 亚型神经氨酸酶开型设计的可能抑制剂。事实上，化合物 8a 对 H1N1 病毒具有很强的神经氨酸酶抑制作用和良好的抗流感活性，IC（50）=2.15μM，EC（50）=0.77μM。这项研究可能为设计更好的神经氨酸酶 1 组抑制剂提供线索。
