MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China; School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
Int J Biol Macromol. 2023 Jun 15;240:124352. doi: 10.1016/j.ijbiomac.2023.124352. Epub 2023 Apr 11.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently posed a serious threat to global public health. Harringtonine (HT), as a small-molecule antagonist, has antiviral activity against a variety of viruses. There is evidence that HT can inhibit the SARS-CoV-2 entry into host cells by blocking the Spike protein and transmembrane protease serine 2 (TMPRSS2). However, the molecular mechanism underlying the inhibition effect of HT is largely elusive. Here, docking and all-atom molecular dynamics simulations were used to investigate the mechanism of HT against the receptor binding domain (RBD) of Spike, TMPRSS2, as well as the complex of RBD and angiotensin-converting enzyme 2 complex (RBD-ACE2). The results reveal that HT binds to all proteins primarily through hydrogen bond and hydrophobic interactions. Binding with HT influences the structural stability and dynamic motility processes of each protein. The interactions of HT with residues N33, H34 and K353 of ACE2, and residue K417 and Y453 of RBD contribute to disrupting the binding affinity between RBD and ACE2, which may hinder the virus entry into host cells. Our research provides molecular insights into the inhibition mechanism of HT against SARS-CoV-2 associated proteins, which will help for the novel antiviral drugs development.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）最近对全球公共卫生构成了严重威胁。作为一种小分子拮抗剂，高三尖杉酯碱（HT）对多种病毒具有抗病毒活性。有证据表明，HT 通过阻断刺突蛋白和跨膜丝氨酸蛋白酶 2（TMPRSS2）来抑制 SARS-CoV-2 进入宿主细胞。然而，HT 抑制作用的分子机制在很大程度上仍不清楚。在这里，我们使用对接和全原子分子动力学模拟来研究 HT 针对 Spike 的受体结合域（RBD）、TMPRSS2 以及 RBD 和血管紧张素转换酶 2 复合物（RBD-ACE2）复合物的抑制机制。结果表明，HT 主要通过氢键和疏水相互作用与所有蛋白质结合。与 HT 的结合影响每个蛋白质的结构稳定性和动态运动过程。HT 与 ACE2 的残基 N33、H34 和 K353 以及 RBD 的残基 K417 和 Y453 的相互作用有助于破坏 RBD 和 ACE2 之间的结合亲和力，这可能阻碍病毒进入宿主细胞。我们的研究为 HT 抑制 SARS-CoV-2 相关蛋白的机制提供了分子见解，这将有助于开发新型抗病毒药物。
