State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Key Laboratory of Natural Pesticides and Chemical Biology, South China Agricultural University, Guangzhou, 510642, China.
J Mol Model. 2013 Dec;19(12):5561-8. doi: 10.1007/s00894-013-2036-0. Epub 2013 Nov 21.
Hemagglutinin (HA) is a membrane protein present on the influenza viral envelope. It is responsible for molecular recognition between the viral particle and the host cell, as well as fusion of the viral envelope to the endosome bilayer. Because it is essential for influenza viral infection and replication, it has become a target for the design of anti-influenza drugs. Previous studies have identified two small molecule HA ligands (CL-385319 and 1L) that inhibit infection with pseudovirus H5N1 with different potency. In order to compare their different inhibitory activities and shed light on drug design targeting the HA protein, we conducted a variety of theoretical calculations, including docking, molecular dynamics simulations, free energy calculations, as well as quantum calculations to investigate interactions between these two ligands and the HA protein. We found that molecule 1L has stronger π-π interactions with the side chains of residues F110₂ and M24₁ compared with molecule CL-385319. We propose that these stronger π-π interactions are responsible for the higher inhibitory activity of molecule 1L. Our calculations will aid drug design studies targeting the HA protein.
血凝素 (HA) 是存在于流感病毒包膜上的一种膜蛋白。它负责病毒粒子与宿主细胞之间的分子识别，以及病毒包膜与内体双层膜的融合。由于它是流感病毒感染和复制所必需的，因此它已成为设计抗流感药物的目标。先前的研究已经确定了两种小分子 HA 配体 (CL-385319 和 1L)，它们以不同的效力抑制假型 H5N1 感染。为了比较它们不同的抑制活性，并阐明针对 HA 蛋白的药物设计，我们进行了各种理论计算，包括对接、分子动力学模拟、自由能计算以及量子计算，以研究这两种配体与 HA 蛋白之间的相互作用。我们发现分子 1L 与残基 F110₂和 M24₁的侧链之间具有更强的 π-π 相互作用，而分子 CL-385319 则没有。我们提出这些更强的 π-π 相互作用是分子 1L 具有更高抑制活性的原因。我们的计算将有助于针对 HA 蛋白的药物设计研究。
