School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea.
Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea.
Eur J Med Chem. 2023 Nov 15;260:115720. doi: 10.1016/j.ejmech.2023.115720. Epub 2023 Aug 18.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) has been targeted for the development of anti-SARS-CoV-2 agents against COVID-19 infection because M processes essential viral polyproteins and plays a key role in SARS-CoV-2 replication. In this study, we report the development of novel SARS-CoV-2 M inhibitors derived from carmofur, a previously identified compound that has shown moderate potency as a covalent inhibitor of SARS-CoV-2 M. To employ a structure-guided drug design strategy, a putative intact binding mode of carmofur at catalytic active site of M was initially predicted by docking simulation. Based on the predicted binding mode, a series of carmofur derivatives aiming to occupy the M substrate binding regions were investigated for structure-activity relationship analysis. As a result, an indole-based derivative, speculated to interact with the S4 binding pocket, 21b (IC = 1.5 ± 0.1 μM) was discovered. Its structure was further modified and evaluated in silico by combining docking simulation, free energy perturbation calculation and subpocket interaction analysis to optimize the interactions at the S2 and S4 binding pockets. Among the newly designed novel derivatives, 21h and 21i showed the best inhibitory potencies against M with IC values of 0.35 and 0.37 μM, respectively. Moreover, their antiviral activities were confirmed with EC values of 20-30 μM in the SARS-CoV-2-infected cell-based assay, suggesting that these novel M inhibitors could be applied as potential lead compounds for the development of substantial anti-SARS-CoV-2 agents.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 主蛋白酶 (M) 已成为开发抗 SARS-CoV-2 药物的靶点，以对抗 COVID-19 感染，因为 M 加工必需的病毒多蛋白，并在 SARS-CoV-2 复制中发挥关键作用。在这项研究中，我们报告了源自卡莫氟的新型 SARS-CoV-2 M 抑制剂的开发，卡莫氟是一种先前被鉴定的化合物，作为 SARS-CoV-2 M 的共价抑制剂具有中等效力。为了采用基于结构的药物设计策略，最初通过对接模拟预测了卡莫氟在 M 的催化活性部位的假定完整结合模式。基于预测的结合模式，研究了一系列旨在占据 M 底物结合区域的卡莫氟衍生物，以进行构效关系分析。结果，发现了一种吲哚基衍生物 21b（IC = 1.5 ± 0.1 μM），推测其与 S4 结合口袋相互作用。其结构通过结合对接模拟、自由能扰动计算和亚口袋相互作用分析进行了进一步的计算机模拟修饰和评估，以优化 S2 和 S4 结合口袋的相互作用。在所设计的新型衍生物中，21h 和 21i 对 M 的抑制作用最强，IC 值分别为 0.35 和 0.37 μM。此外，它们在 SARS-CoV-2 感染细胞测定中的 EC 值为 20-30 μM，证实了它们的抗病毒活性，这表明这些新型 M 抑制剂可作为开发有效抗 SARS-CoV-2 药物的潜在先导化合物。
