Anhui Provincial Engineering Laboratory of Silicon-Based Materials, Bengbu University, Caoshan Road 1866, Bengbu, Anhui 233030, PR China.
Institute for Drug Research, The Hebrew University, Jerusalem 9112001, Israel.
J Phys Chem Lett. 2021 Feb 25;12(7):1793-1802. doi: 10.1021/acs.jpclett.0c03119. Epub 2021 Feb 12.
In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD with an IC of 1.81 ± 0.04 μM and inhibit SARS-CoV-2 viral infection in cells with an EC of 71.6 μM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.
在寻找 COVID-19 抑制剂的过程中，我们以人类血管紧张素转换酶 2（ACE2）受体与 SARS-CoV-2 的刺突受体结合域（S1-RBD）之间的相互作用作为靶点。对天然化合物库进行虚拟筛选，鉴定出 Kobophenol A 是一种潜在的抑制剂。Kobophenol A 随后被发现可以阻断 ACE2 受体与 S1-RBD 的相互作用，IC 为 1.81±0.04 μM，并以 EC 为 71.6 μM 抑制细胞中的 SARS-CoV-2 病毒感染。盲目对接计算确定了两个潜在的结合位点，分子动力学模拟预测 Kobophenol A 与刺突/ACE2 界面和 ACE2 疏水性口袋的结合自由能分别为-19.0±4.3 和-24.9±6.9 kcal/mol。总之，通过对接研究鉴定出的 Kobophenol A 是第一种通过阻断 S1-RBD 与宿主 ACE2 受体的结合来抑制 SARS-CoV-2 与细胞结合的化合物，因此可能成为对抗 COVID-19 的良好先导化合物。
