Insights from investigating the interactions of natural product inhibitors with neuraminidase of the 2009 H1N1 influenza virus

基于2009 H1N1神经氨酸酶天然产物抑制剂的作用模式的研究

Neuraminidase(NA) plays a biologically vital role in the replication of influenza virus, and NA inhibitors(NAIs) are most widely used in the clinical anti-flu therapy. NA of 2009 H1 N1 influenza virus(09 N1) possesses a different substrate-binding cavity compared with other NA subtypes, making 09 N1 a more appropriate starting point for the discovery of potent 09 N1 inhibitors. As natural products are of great structural diversity, research on the interaction between natural NAIs and 09 N1 can throw light on the design of new structural NAIs. In this study, we, for the first time, conducted molecular docking procedure with GOLD on 10 natural inhibitors to 09 N1, and acquired their binding modes with 09 N1. The docking results showed that the active site S1 was important in the binding of NAIs to 09 N1. Then five scaffolds were extracted from these NAIs with interactions to site S1, and these could be used in the structural modification of NAIs. Besides, we found that the addition of H-bonding interaction with the active site could improve the NA inhibitory activity of NAIs, and it might be the reason why the approved NAIs showed high efficiency. Two terminal hydrophobic sites(Terminal 1 and Terminal 2) with no interactions to the approved NAI zanamivir were found in the 09 N1 active cavity, and four NAIs were first found to bind with the terminals. Till now, there are few studies on the meaning of Terminal 2 in the binding of NAI to NA, which could be a new direction for the rational design of NAIs.

神经氨酸酶(NA)在流感病毒的复制过程中发挥关键作用,临床上应用最多的抗流感病毒药物均为NA抑制剂(NAIs)。当前流行的2009H1N1流感病毒的NA(09N1)与其他亚型NA的底物结合空腔存在差异,故以09N1结构为基础开发对09N1高效的抑制剂更为适宜。由于天然产物的结构多样,分析天然产物抑制剂与09N1的作用模式可为新型抑制剂的发现提供思路。本研究利用GOLD软件对10个天然产物NAIs与09N1进行了分子对接研究,并首次获得它们与09N1的结合模式。对接结果表明,活性位点S1区对于NAIs同09N1的结合非常重要,从这些NAIs中抽提出5个与S1区发生作用的结构骨架,可用于新型抑制剂的结构设计。此外还发现,增强同活性位点的氢键作用可提高NAIs的抑制活性,这可能是上市药物具有更高活性的原因。在09N1的活性空腔中发现同上市药物扎那米韦无相互作用的两处末端疏水位点(Terminal 1和Terminal 2),并首次揭示4个天然产物能结合于该位点。迄今为止,关于Terminal 2对于NAI与NA结合意义的研究还鲜见报道,可作为NAIs合理药物设计研究的新方向。