Data_Sheet_1_Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2.docx

The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, a very small number of remedies have been to be found effective against SARS-CoV-2 infection. Therefore, further research is required to achieve a lasting solution against this deadly disease. Repurposing available drugs and evaluating natural product inhibitors against target proteins of SARS-CoV-2 could be an effective approach to accelerate drug discovery and development. With this strategy in mind, we derived Marine Natural Products (MNP)-based drug-like small molecules and evaluated them against three major target proteins of the SARS-CoV-2 virus replication cycle. A drug-like database from MNP library was generated using Lipinski’s rule of five and ADMET descriptors. A total of 2,033 compounds were obtained and were subsequently subjected to molecular docking with 3CLpro, PLpro, and RdRp. The docking analyses revealed that a total of 14 compounds displayed better docking scores than the reference compounds and have significant molecular interactions with the active site residues of SARS-CoV-2 virus targeted proteins. Furthermore, the stability of docking-derived complexes was analyzed using molecular dynamics simulations and binding free energy calculations. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, binding affinity, and molecular interactions. Our investigation identified two hit compounds against each targeted proteins displaying stable behavior, higher binding affinity and key residual molecular interactions, with good in silico pharmacokinetic properties, therefore can be considered for further in vitro studies.

新冠病毒（SARS-CoV-2）引发的严重急性呼吸综合征（COVID-19）的迅速蔓延，已成为全球性的卫生紧急事件。遗憾的是，迄今为止，能够有效抵抗SARS-CoV-2感染的药物寥寥无几。因此，为实现对这一致命疾病的持久解决方案，迫切需要进行进一步的研究。重新利用现有药物并评估针对SARS-CoV-2病毒复制周期靶蛋白的自然产物抑制剂，可能是一种有效加速药物发现和开发的途径。本着这一策略，我们基于海洋天然产物（MNP）提取了具有药物特性的小分子，并对其进行了针对SARS-CoV-2病毒复制周期三大靶蛋白的评估。利用Lipinski的五条规则和ADMET描述符，构建了一个基于MNP库的药物数据库。共获得2033个化合物，随后对它们进行了与3CLpro、PLpro和RdRp的分子对接。对接分析显示，共有14个化合物的对接评分优于对照化合物，并且与SARS-CoV-2病毒靶蛋白的活性位点残基具有显著的分子相互作用。此外，通过分子动力学模拟和结合自由能计算分析了对接得到的复合物的稳定性。分析结果显示，针对每个靶蛋白均发现了两个具有稳定行为、高结合亲和力和关键残基分子相互作用的活性化合物。我们的研究识别出针对每个靶蛋白的活性化合物，显示出良好的虚拟药代动力学特性，因此可考虑进行进一步的体外研究。