Department of Chemistry, School of Sciences and Engineering, American University in Cairo, AUC Avenue, SSE # 1184, P.O. Box 74, New Cairo, 11835, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, 11837, Cairo, Egypt.
Comput Biol Med. 2021 Jul;134:104468. doi: 10.1016/j.compbiomed.2021.104468. Epub 2021 May 11.
Corona Virus 2019 Disease (COVID-19) is a rapidly emerging pandemic caused by a newly discovered beta coronavirus, called Sever Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2). SARS CoV-2 is an enveloped, single stranded RNA virus that depends on RNA-dependent RNA polymerase (RdRp) to replicate. Therefore, SARS CoV-2 RdRp is considered as a promising target to cease virus replication. SARS CoV-2 polymerase shows high structural similarity to Hepatitis C Virus-1b genotype (HCV-1b) polymerase. Arising from the high similarity between SARS CoV-2 RdRp and HCV NS5B, we utilized the reported small-molecule binders to the palm subdomain of HCV NS5B (genotype 1b) to generate a high-quality DEKOIS 2.0 benchmark set and conducted a benchmarking analysis against HCV NS5B. The three highly cited and publicly available docking tools AutoDock Vina, FRED and PLANTS were benchmarked. Based on the benchmarking results and analysis via pROC-Chemotype plot, PLANTS showed the best screening performance and can recognize potent binders at the early enrichment. Accordingly, we used PLANTS in a prospective virtual screening to repurpose both the FDA-approved drugs (DrugBank) and the HCV-NS5B palm subdomain binders (BindingDB) for SARS CoV-2 RdRp palm subdomain. Further assessment by molecular dynamics simulations for 50 ns recommended diosmin (from DrugBank) and compound 3 (from BindingDB) to be the best potential binders to SARS CoV-2 RdRp palm subdomain. The best predicted compounds are recommended to be biologically investigated against COVID-19. In conclusion, this work provides in-silico analysis to propose possible SARS CoV-2 RdRp palm subdomain binders recommended as a remedy for COVID-19. Up-to-our knowledge, this study is the first to propose binders at the palm subdomain of SARS CoV2 RdRp. Furthermore, this study delivers an example of how to make use of a high quality custom-made DEKOIS 2.0 benchmark set as a procedure to elevate the virtual screening success rate against a vital target of the rapidly emerging pandemic.
新型冠状病毒病（COVID-19）是由一种新发现的贝塔冠状病毒引起的迅速出现的大流行，称为严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）。SARS-CoV-2 是一种包膜、单链 RNA 病毒，依赖 RNA 依赖性 RNA 聚合酶（RdRp）进行复制。因此，SARS-CoV-2 RdRp 被认为是阻止病毒复制的有希望的靶标。SARS-CoV-2 聚合酶与丙型肝炎病毒-1b 基因型（HCV-1b）聚合酶具有很高的结构相似性。由于 SARS-CoV-2 RdRp 与 HCV NS5B 之间存在很高的相似性，我们利用报道的小分子结合物来结合 HCV NS5B 的手掌亚结构域（基因型 1b），生成了高质量的 DEKOIS 2.0 基准集，并对 HCV NS5B 进行了基准分析。对三个高度引用和公开可用的对接工具 AutoDock Vina、FRED 和 PLANTS 进行了基准测试。基于基准测试结果和通过 pROC-Chemotype 图进行的分析，PLANTS 显示出最佳的筛选性能，并可以在早期富集时识别出有效的结合物。因此，我们在一个前瞻性虚拟筛选中使用 PLANTS，将 FDA 批准的药物（DrugBank）和 HCV-NS5B 手掌亚结构域结合物（BindingDB）重新用于 SARS-CoV-2 RdRp 手掌亚结构域。通过 50ns 的分子动力学模拟进一步评估，推荐地奥司明（来自 DrugBank）和化合物 3（来自 BindingDB）作为 SARS-CoV-2 RdRp 手掌亚结构域的最佳潜在结合物。建议对最佳预测化合物进行生物研究，以对抗 COVID-19。总之，这项工作提供了计算分析，提出了推荐用于治疗 COVID-19 的 SARS-CoV-2 RdRp 手掌亚结构域潜在结合物。据我们所知，这项研究首次提出了 SARS-CoV2 RdRp 手掌亚结构域的结合物。此外，这项研究提供了一个如何利用高质量定制的 DEKOIS 2.0 基准集作为程序来提高针对快速出现的大流行的重要靶标的虚拟筛选成功率的示例。
