IEEE/ACM Trans Comput Biol Bioinform. 2021 Jul-Aug;18(4):1281-1289. doi: 10.1109/TCBB.2021.3076259. Epub 2021 Aug 6.
The novel SARS-CoV-2 uses ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in S protein and ACE2 interface is crucial in search of effective drugs to prevent viral entry. In this study, we employed molecular dynamics simulations in mixed solvents together with virtual screening to identify small molecules that could be potential inhibitors of S protein -ACE2 interaction. Observation of organic probe molecule localization during the simulations revealed multiple sites at the S protein surface related to small molecule, antibody, and ACE2 binding. In addition, a novel conformation of the S protein was discovered that could be stabilized by small molecules to inhibit attachment to ACE2. The most promising binding site on RBD-ACE2 interface was targeted with virtual screening and top-ranked compounds (DB08248, DB02651, DB03714, and DB14826) are suggested for experimental testing. The protocol described here offers an extremely fast method for characterizing key proteins of a novel pathogen and for the identification of compounds that could inhibit or accelerate spreading of the disease.
新型 SARS-CoV-2 利用 ACE2（血管紧张素转化酶 2）受体作为进入点。对 S 蛋白受体结合域（RBD）与 ACE2 受体相互作用和药物再利用的深入了解加速了新型 SARS-CoV-2 感染的药物发现。在 S 蛋白和 ACE2 界面中寻找小分子结合位点对于寻找预防病毒进入的有效药物至关重要。在这项研究中，我们采用混合溶剂中的分子动力学模拟和虚拟筛选来识别可能成为 S 蛋白-ACE2 相互作用潜在抑制剂的小分子。在模拟过程中观察有机探针分子的定位，揭示了与小分子、抗体和 ACE2 结合相关的 S 蛋白表面的多个位点。此外，还发现了一种新的 S 蛋白构象，这种构象可以通过小分子稳定化来抑制与 ACE2 的附着。利用虚拟筛选对 RBD-ACE2 界面上最有前途的结合位点进行了靶向，建议对排名靠前的化合物（DB08248、DB02651、DB03714 和 DB14826）进行实验测试。这里描述的方案为表征新型病原体的关键蛋白提供了一种极其快速的方法，并为鉴定可能抑制或加速疾病传播的化合物提供了方法。
