A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro

• Published in: PLoS computational biology Vol. 16; no. 12; p. e1008489
• Main Authors: Zhang, Haiping, Yang, Yang, Li, Junxin, Wang, Min, Saravanan, Konda Mani, Wei, Jinli, Tze-Yang Ng, Justin, Tofazzal Hossain, Md, Liu, Maoxuan, Zhang, Huiling, Ren, Xiaohu, Pan, Yi, Peng, Yin, Shi, Yi, Wan, Xiaochun, Liu, Yingxia, Wei, Yanjie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.12.2020; Public Library of Science (PLoS)
• Subjects: Acute lymphatic leukemia; Acute lymphoblastic leukemia; Adenosine; Aminopterin - analogs & derivatives; Aminopterin - chemistry; Aminopterin - pharmacology; Amoxicillin; Animals; Antibiotics; Antiviral Agents - pharmacology; Azithromycin; Azithromycin - chemistry; Azithromycin - pharmacology; Binding sites; Biology and life sciences; China; Chlorocebus aethiops; Computer Simulation; Control; Coordination numbers; Coronaviruses; COVID-19; COVID-19 - drug therapy; Deep Learning; Drug discovery; Drug Evaluation, Preclinical - methods; Drug Repositioning; Drugs; Epidemics; Free energy; Hepatitis; Hepatitis C; Hepatitis C virus; Hydrogen bonds; Inhibitors; Innovations; Leukemia; Libraries; Ligands; Liver diseases; Medicine and health sciences; Methods; Molecular Dynamics Simulation; Molecular weight; Nucleotide analogs; Nucleotides; Penicillin; Physical Sciences; Proteins; Replication; Research and Analysis Methods; RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-directed RNA polymerase; SARS-CoV-2 - physiology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Simulation; Technology application; Vero Cells; Viral diseases; Virus Replication - drug effects; Viruses; China
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1008489

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC 50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.