The novel SARS-CoV-2 uses the 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 the S protein and ACE2 interface is crucial in the 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 a 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 the 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 the spreading of the disease.

中文翻译：

---

在混合溶剂中通过分子动力学模拟检测SARS-CoV-2 Spike蛋白受体结合结构域上的结合位点。

新型SARS-CoV-2使用ACE2（血管紧张素转换酶2）受体作为切入点。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见解加速了新型SARS-CoV-2感染的药物发现。在S蛋白和ACE2界面中发现小分子结合位点对于寻找有效的药物来预防病毒进入至关重要。在这项研究中，我们在混合溶剂中采用了分子动力学模拟，并进行了虚拟筛选，以鉴定可能是S蛋白ACE2相互作用的潜在抑制剂的小分子。在模拟过程中观察到的有机探针分子的位置揭示了S蛋白表面上的多个位点，这些位点与小分子，抗体和ACE2的结合有关。此外，发现了一种新的S蛋白构象，该构象可以被小分子稳定以抑制与ACE2的结合。RBD-ACE2接口上最有希望的结合位点被虚拟筛选作为目标，建议对实验性排名最高的化合物（DB08248，DB02651，DB03714和DB14826）进行筛选。此处描述的协议提供了一种非常快速的方法，用于表征新型病原体的关键蛋白并鉴定可抑制或加速疾病传播的化合物。