{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:34:09Z","timestamp":1776321249951,"version":"3.50.1"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>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<jats:italic>in vitro<\/jats:italic>with EC<jats:sub>50<\/jats:sub>values of 0.008\u03bcM and 9.453 \u03bcM, 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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008489","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T18:37:26Z","timestamp":1609439846000},"page":"e1008489","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":54,"title":["A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in 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vitro.","author":"M Wang","year":"2020","journal-title":"Cell Research"},{"key":"pcbi.1008489.ref006","article-title":"Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir","author":"W Yin","year":"2020","journal-title":"Science (80-)."},{"key":"pcbi.1008489.ref007","article-title":"Compassionate Use of Remdesivir for Patients with Severe Covid-19","author":"J Grein","year":"2020","journal-title":"N Engl J Med"},{"key":"pcbi.1008489.ref008","article-title":"Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors.","author":"RN Kirchdoerfer","year":"2019","journal-title":"Nat Commun."},{"key":"pcbi.1008489.ref009","article-title":"Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods","author":"C Wu","year":"2020","journal-title":"Acta Pharm Sin B"},{"key":"pcbi.1008489.ref010","first-page":"eabb7498","article-title":"Structure of the RNA-dependent RNA polymerase from COVID-19 virus","author":"Y Gao","year":"2020","journal-title":"Science (80-)."},{"key":"pcbi.1008489.ref011","article-title":"In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing","author":"Y Kumar","year":"2020","journal-title":"J Infect Public Health"},{"key":"pcbi.1008489.ref012","article-title":"In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins","author":"I Maffucci","year":"2020","journal-title":"J Proteome Res"},{"key":"pcbi.1008489.ref013","article-title":"An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors.","author":"A Trezza","year":"2020","journal-title":"Sci Rep."},{"key":"pcbi.1008489.ref014","article-title":"In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Consensus Ranking.","author":"CN Cavasotto","year":"2020","journal-title":"Mol Inform"},{"key":"pcbi.1008489.ref015","article-title":"IVS2vec: A tool of Inverse Virtual Screening based on word2vec and deep learning techniques.","author":"H Zhang","year":"2019","journal-title":"Methods"},{"key":"pcbi.1008489.ref016","article-title":"Autodock Vina.","author":"BR Brooks","year":"2009","journal-title":"J Comput Chem"},{"key":"pcbi.1008489.ref017","article-title":"Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial","author":"P Gautret","year":"2020","journal-title":"Int J Antimicrob Agents"},{"key":"pcbi.1008489.ref018","article-title":"Should azithromycin be used to treat COVID-19? A rapid review.","author":"K Gbinigie","year":"2020","journal-title":"BJGP Open."},{"key":"pcbi.1008489.ref019","article-title":"Sofosbuvir: A novel treatment option for chronic hepatitis C infection.","author":"HK Bhatia","year":"2014","journal-title":"J Pharmacol Pharmacother."},{"key":"pcbi.1008489.ref020","article-title":"Clofarabine combinations as acute myeloid leukemia salvage therapy","author":"S Faderl","year":"2008","journal-title":"Cancer"},{"key":"pcbi.1008489.ref021","article-title":"Improving the Efficiency of Ligand-Binding Protein Design with Molecular Dynamics Simulations.","author":"EP Barros","year":"2019","journal-title":"J Chem Theory Comput."},{"key":"pcbi.1008489.ref022","article-title":"DeepBindRG: A deep learning based method for estimating effective protein-ligand affinity.","author":"H Zhang","year":"2019","journal-title":"PeerJ"},{"key":"pcbi.1008489.ref023","article-title":"Development of new agents for peripheral T-cell lymphoma","author":"Y Ito","year":"2019","journal-title":"Expert Opinion on Biological Therapy"},{"key":"pcbi.1008489.ref024","article-title":"Evaluation of the pharmacokinetics, preclinical and clinical efficacy of pralatrexate for the treatment of T-cell lymphoma.","author":"FM Foss","year":"2011","journal-title":"Expert Opinion on Drug Metabolism and Toxicology"},{"key":"pcbi.1008489.ref025","article-title":"DNA and RNA synthesis: Antifolates.","author":"IM Kompis","year":"2005","journal-title":"Chemical Reviews"},{"key":"pcbi.1008489.ref026","article-title":"I-TASSER server for protein 3D structure prediction","author":"Y. Zhang","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1008489.ref027","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.bmcl.2008.01.007","article-title":"Novel HCV NS5B polymerase inhibitors derived from 4-(1\u2032,1\u2032-dioxo-1\u2032,4\u2032-dihydro-1\u2032\u03bb6-benzo [1\u2032,2\u2032,4\u2032]thiadiazin-3\u2032-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: Exploration of 7\u2032-substitution of benzothiadiazine.","volume":"18","author":"Y Zhou","year":"2008","journal-title":"Bioorganic Med Chem Lett"},{"key":"pcbi.1008489.ref028","article-title":"COFACTOR: An accurate comparative algorithm for structure-based protein function annotation","author":"A Roy","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1008489.ref029","article-title":"Mol2vec: Unsupervised Machine Learning Approach with Chemical Intuition.","author":"S Jaeger","year":"2018","journal-title":"J Chem Inf Model."},{"key":"pcbi.1008489.ref030","article-title":"PDB-wide collection of binding data: Current status of the PDBbind database","author":"Z Liu","year":"2015","journal-title":"Bioinformatics"},{"key":"pcbi.1008489.ref031","article-title":"Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","author":"GM Morris","year":"2009","journal-title":"J Comput Chem"},{"key":"pcbi.1008489.ref032","article-title":"Pymol: An open-source molecular graphics tool.","author":"WL DeLano","year":"2002","journal-title":"CCP4 Newsl Protein Crystallogr."},{"key":"pcbi.1008489.ref033","article-title":"Metadynamics: A method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science.","author":"A Laio","year":"2008","journal-title":"Reports Prog Phys"},{"key":"pcbi.1008489.ref034","article-title":"An Efficient Metadynamics-Based Protocol to Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands.","author":"N Saleh","year":"2017","journal-title":"J Chem Inf Model"},{"key":"pcbi.1008489.ref035","article-title":"Dynamic undocking and the quasi-bound state as tools for drug discovery.","author":"S Ruiz-Carmona","year":"2017","journal-title":"Nat Chem."},{"key":"pcbi.1008489.ref036","article-title":"GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation.","author":"B Hess","year":"2008","journal-title":"J Chem."},{"key":"pcbi.1008489.ref037","article-title":"Generation of accurate protein loop conformations through low-barrier molecular dynamics","author":"V Hornak","year":"2003","journal-title":"Proteins Struct Funct Genet"},{"key":"pcbi.1008489.ref038","article-title":"ACPYPE\u2014AnteChamber PYthon Parser interfacE.","author":"AW Sousa Da Silva","year":"2012","journal-title":"BMC Res Notes."},{"key":"pcbi.1008489.ref039","article-title":"Automatic atom type and bond type perception in molecular mechanical calculations","author":"J Wang","year":"2006","journal-title":"J Mol Graph Model"},{"key":"pcbi.1008489.ref040","article-title":"Comparison of simple potential functions for simulating liquid water","author":"WL Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"key":"pcbi.1008489.ref041","article-title":"GROMACS: Fast, flexible, and free","author":"D Van Der Spoel","year":"2005","journal-title":"Journal of Computational Chemistry"},{"key":"pcbi.1008489.ref042","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems.","author":"T Darden","year":"1993","journal-title":"J Chem Phys"},{"key":"pcbi.1008489.ref043","article-title":"LINCS: A Linear Constraint Solver for molecular simulations","author":"B Hess","year":"1997","journal-title":"J Comput Chem"},{"key":"pcbi.1008489.ref044","article-title":"PLUMED 2: New feathers for an old bird","author":"GA Tribello","year":"2014","journal-title":"Comput Phys Commun"},{"key":"pcbi.1008489.ref045","article-title":"Gnuplot 4.6.","author":"T Williams","year":"2012","journal-title":"Softw Man"},{"key":"pcbi.1008489.ref046","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"key":"pcbi.1008489.ref047","article-title":"VMD: Visual molecular dynamics","author":"W Humphrey","year":"1996","journal-title":"J Mol Graph"},{"key":"pcbi.1008489.ref048","doi-asserted-by":"crossref","unstructured":"Visualizer DS. v4. 0.100. 13345. Accelrys Software Inc. 2005.","DOI":"10.1049\/cp:20050764"},{"key":"pcbi.1008489.ref049","unstructured":"Landrum G. RDKit: Open-source Cheminformatics. In: Http:\/\/Www.Rdkit.Org\/. 2006. doi: 10.2307\/3592822"},{"key":"pcbi.1008489.ref050","article-title":"Algorithms for hierarchical clustering: An overview.","author":"F Murtagh","year":"2012","journal-title":"Wiley Interdiscip Rev Data Min Knowl Discov"},{"key":"pcbi.1008489.ref051","doi-asserted-by":"crossref","DOI":"10.1007\/s12250-017-3958-y","article-title":"Development of a reverse transcription quantitative polymerase chain reaction-based assay for broad coverage detection of African and Asian Zika virus lineages","author":"Y Yang","year":"2017","journal-title":"Virol Sin"},{"key":"pcbi.1008489.ref052","article-title":"A simple method of estimating fifty per cent endpoints","author":"LJ Reed","year":"1938","journal-title":"Am J Epidemiol"},{"key":"pcbi.1008489.ref053","article-title":"The Time Sequences of Oral and Fecal Viral Shedding of Coronavirus Disease 2019 (COVID-19) Patients.","author":"F Zhao","year":"2020","journal-title":"Gastroenterology"},{"key":"pcbi.1008489.ref054","doi-asserted-by":"crossref","DOI":"10.1007\/s13238-013-3096-8","article-title":"The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists.","author":"Y Yang","year":"2013","journal-title":"Protein Cell."},{"key":"pcbi.1008489.ref055","doi-asserted-by":"crossref","DOI":"10.1038\/srep17554","article-title":"Middle East respiratory syndrome coronavirus ORF4b protein inhibits type i interferon production through both cytoplasmic and nuclear targets.","author":"Y Yang","year":"2015","journal-title":"Sci Rep."}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008489","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T13:53:16Z","timestamp":1724161996000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008489"}},"subtitle":[],"editor":[{"given":"Avner","family":"Schlessinger","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":55,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008489","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,31]]}}}