Facilitating SARS CoV-2 RNA-Dependent RNA polymerase (RdRp) drug discovery by the aid of HCV NS5B palm subdomain binders: In silico approaches and benchmarking

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 envel-oped, single stranded RNA virus that depends on RNA-dependent RNA polymerase (RdRp) to replicate. There-fore, 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 biolog-ically 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.

Automated summary

This study conducted in-silico analysis to propose potential SARS CoV-2 RdRp palm subdomain binders as a remedy for COVID-19. By utilizing a high-quality custom-made DEKOIS 2.0 benchmark set, successful virtual screening was performed, recommending several potential binders.