Yazdani Mohsen, Jafari Ameneh, Mahdian Soodeh, Namazi Mohsen, Gharaghani Sajjad
Laboratory of Bioinformatics and Drug Design, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. Box: 15179/64311, Tehran, Iran.
J Mol Liq. 2023 Apr 1;375:121345. doi: 10.1016/j.molliq.2023.121345. Epub 2023 Feb 1.
The lack of effective treatment remains a bottleneck in combating the current coronavirus family pandemic, particularly coronavirus 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection of host cells by SARS-CoV-2 is mediated by the binding of its receptor-binding domain (RBD) on the spike (S) glycoprotein to the host angiotensin-converting enzyme (ACE2) receptor. As all developed and available vaccines against COVID-19 do not provide long-term immunity, the creation of an effective drug for the treatment of COVID-19 is necessary and cannot be ignored. Therefore, the aim of this study is to present a computational screening method to identify potential inhibitor candidates with a high probability of blocking the binding of RBD to the ACE2 receptor. Pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations, and binding free-energy analyses were performed to identify potential inhibitor candidates against ACE2/SARS-CoV-2. In conclusion, we propose the compound PubChem-84280085 as a potential inhibitor of protein-protein interactions to disrupt the binding of the SARS-CoV-2-RBD to the ACE2 receptor.
缺乏有效的治疗方法仍然是抗击当前冠状病毒家族大流行的一个瓶颈，尤其是由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）。SARS-CoV-2对宿主细胞的感染是通过其刺突（S）糖蛋白上的受体结合域（RBD）与宿主血管紧张素转换酶（ACE2）受体的结合来介导的。由于所有已研发和可用的COVID-19疫苗都不能提供长期免疫力，因此开发一种有效的COVID-19治疗药物是必要且不容忽视的。因此，本研究的目的是提出一种计算筛选方法，以识别具有高概率阻断RBD与ACE2受体结合的潜在抑制剂候选物。进行了药效团映射、分子对接、分子动力学（MD）模拟和结合自由能分析，以识别针对ACE2/SARS-CoV-2的潜在抑制剂候选物。总之，我们提出化合物PubChem-84280085作为一种潜在的蛋白质-蛋白质相互作用抑制剂，以破坏SARS-CoV-2-RBD与ACE2受体的结合。
