School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, 250200, China.
Interdiscip Sci. 2018 Jun;10(2):430-437. doi: 10.1007/s12539-017-0239-2. Epub 2017 Jun 19.
Influenza virus is a major causative agent of respiratory viral infections, and RNA polymerase catalyzes its replication and transcription activities in infected cell nuclei. Since it is highly conserved in all virus strains, RNA polymerase becomes a key target of anti-influenza virus agents. Although experimental studies have revealed the good inhibitory activity of endonuclease inhibitors to RNA polymerase, the mechanism is still unclear. In this study, the docking and molecular dynamics simulations have been performed to explore the interaction of three kinds of endonuclease inhibitors with the subunit (PA) of RNA polymerase. Our calculations indicate that all these endonuclease inhibitors can bind to the binding pocket of PA, in which the electronegative oxygen atoms of the inhibitors form a chelated structure with the two Mn cations of the active center. The most important interaction between these inhibitors and PA is electrostatic interaction. The electron density of the chelate oxygen atoms determines the magnitude of the electrostatic energy, and the chelated structure and orientation of inhibitors depend largely on the distance between the chelate oxygen atoms.
流感病毒是引发呼吸道病毒感染的主要病原体，而 RNA 聚合酶在感染细胞的细胞核中催化其复制和转录活动。由于其在所有病毒株中都高度保守，因此 RNA 聚合酶成为抗流感病毒药物的关键靶标。尽管实验研究表明内切核酸酶抑制剂对 RNA 聚合酶具有良好的抑制活性，但作用机制尚不清楚。在这项研究中，我们进行了对接和分子动力学模拟，以探究三种内切核酸酶抑制剂与 RNA 聚合酶亚基（PA）的相互作用。我们的计算表明，所有这些内切核酸酶抑制剂都可以与 PA 的结合口袋结合，其中抑制剂的带负电荷的氧原子与活性中心的两个 Mn 阳离子形成螯合结构。这些抑制剂与 PA 之间最重要的相互作用是静电相互作用。螯合氧原子的电子密度决定了静电能的大小，而抑制剂的螯合结构和取向在很大程度上取决于螯合氧原子之间的距离。
