Department of Mechanical Engineering and Mechanics, Bethlehem, Pennsylvania.
Department of Mechanical Engineering and Mechanics, Bethlehem, Pennsylvania; Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania.
Biophys J. 2021 Jul 20;120(14):2793-2804. doi: 10.1016/j.bpj.2021.06.016. Epub 2021 Jun 30.
The ongoing coronavirus disease 19 (COVID-19) pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host-cell receptor angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the metastable, prefusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.
正在持续的 2019 冠状病毒病（COVID-19）大流行已感染数百万人，夺走数十万人的生命，并引发全球卫生紧急状况。了解严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）的感染机制对于开发潜在的治疗方法和疫苗至关重要。感染过程是由 SARS-CoV-2 受体结合域（RBD）与宿主细胞受体血管紧张素转换酶 2（ACE2）的直接结合引发的。人们已经做出许多努力来设计或重新利用治疗方法来使 RBD 或 ACE2 失活并阻止初始结合。除了直接抑制策略外，小分子化合物可能能够干扰和破坏 ACE2-RBD 的亚稳定预融合复合物。这种方法可以用于在病毒感染的早期阶段阻止其进一步进展。在这项研究中，采用分子对接来分析两种化学化合物 SSAA09E2 和尼洛替尼与 ACE2-RBD 复合物的可药用口袋的结合。通过分子动力学模拟分析了干扰 ACE2-RBD 复合物导致的结构变化。结果表明，尼洛替尼和 SSAA09E2 均可诱导 ACE2-RBD 复合物发生显著的构象变化，干扰氢键，并影响蛋白质的柔韧性。此外，本征动力学分析表明，小分子的存在可以引发可能使 ACE2-RBD 复合物失稳的大规模构象变化。
