Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.
J Mol Model. 2012 Aug;18(8):3445-53. doi: 10.1007/s00894-011-1349-0. Epub 2012 Jan 27.
A new strain of influenza A (H1N1) virus is a major cause of morbidity and mortality around the world. The neuraminidase of the influenza virus has been the most potential target for the anti-influenza drugs such as oseltamivir and zanamivir. However, the emergence of drug-resistant variants of these drugs makes a pressing need for the development of new neuraminidase inhibitors for controlling illness and transmission. Here a 3D structure model of H1N1 avian influenza virus neuraminidase type 1 (N1) was constructed based on the structure of the template H5N1 avian influenza virus N1. Upon application of virtual screening technique for N1 inhibitors, two novel compounds (ZINC database ID: ZINC02128091, ZINC02098378) were found as the most favorable interaction energy with N1. Docking results showed that the compounds bound not only in the active pocket, but also in a new hydrophobic cave which contains Arg368, Trp399, Ile427, Pro431 and Lys432 of N1. Our result suggested that both of the screened compounds containing the hydrophobic group bring a strong conjugation effect with Arg293, Arg368 Lys432 of N1 by pi-pi interaction. However, the control inhibitors zanamivir and oseltamivir do not have this effect. The details of N1-compound binding structure obtained will be valuable for the development of a new anti-influenza virus agent.
一种新型甲型流感病毒（H1N1）是全球发病率和死亡率的主要原因。流感病毒的神经氨酸酶一直是奥司他韦和扎那米韦等抗流感药物最有潜力的靶点。然而，这些药物的耐药变异株的出现迫切需要开发新的神经氨酸酶抑制剂来控制疾病和传播。本研究基于 H5N1 禽流感病毒 N1 的结构模板，构建了 H1N1 禽流感病毒 N1 的三维结构模型。应用 N1 抑制剂的虚拟筛选技术，发现了两种新型化合物（ZINC 数据库 ID：ZINC02128091、ZINC02098378）与 N1 具有最有利的相互作用能。对接结果表明，这些化合物不仅结合在活性口袋中，还结合在一个新的疏水性洞穴中，该洞穴包含 N1 的 Arg368、Trp399、Ile427、Pro431 和 Lys432。研究结果表明，两种筛选出的含有疏水基团的化合物通过π-π 相互作用与 N1 的 Arg293、Arg368 和 Lys432 形成强烈的共轭效应。然而，对照抑制剂扎那米韦和奥司他韦没有这种作用。获得的 N1-化合物结合结构的细节将对开发新型抗流感病毒药物具有重要价值。
