Industrial Development Graduate Program of College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300193, Taiwan.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan.
Int J Mol Sci. 2024 Jun 1;25(11):6105. doi: 10.3390/ijms25116105.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC values of 8.8 μM, 6.7 μM, and 7.6 μM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC = 5.9 μM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC of 9.3 μM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致当前冠状病毒病大流行的罪魁祸首。随着变异株的快速进化，寻找有效的刺突蛋白抑制剂是合乎逻辑和至关重要的优先事项。血管紧张素转换酶 2（ACE2）已被确定为 SARS-CoV-2 病毒进入的功能受体，因此与刺突蛋白-ACE2 相互作用相关的治疗方法在抑制病毒感染方面具有很高的可行性。我们的计算机辅助药物设计（CADD）方法精心分析了美国国立癌症研究所（NCI）数据库中超过 260,000 种化合物记录，以确定潜在的刺突抑制剂。刺突蛋白受体结合域（RBD）被选为我们虚拟筛选过程的靶蛋白。在基于细胞的验证中，使用携带报告基因的 SARS-CoV-2 假病毒来筛选有效化合物。最终，化合物 C2、C8 和 C10 对 SARS-CoV-2 表现出显著的抗病毒活性，估计 EC 值分别为 8.8 μM、6.7 μM 和 7.6 μM。以上述化合物为模板，生成了 10 个衍生物，强大的生物测定结果表明 C8.2（EC=5.9 μM）表现出最强的抗病毒功效。化合物 C8.2 对奥密克戎变异株也表现出抑制活性，EC 值为 9.3 μM。因此，CADD 方法成功发现了与刺突蛋白 RBD 结合并能够抑制病毒感染的先导化合物。
