{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:15:37Z","timestamp":1772172937856,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009384","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000}}],"reference-count":96,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"department of biotechnology","award":["Core Funding, National Institute of Immunology"],"award-info":[{"award-number":["Core Funding, National Institute of Immunology"]}]},{"DOI":"10.13039\/501100008762","name":"tamil nadu state council for higher education","doi-asserted-by":"publisher","award":["File. No. RGP\/2019-20\/ALU\/HECP-0049"],"award-info":[{"award-number":["File. No. RGP\/2019-20\/ALU\/HECP-0049"]}],"id":[{"id":"10.13039\/501100008762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order\n                    <jats:italic>Nidovirales<\/jats:italic>\n                    possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using\n                    <jats:italic>in silico<\/jats:italic>\n                    tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009384","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T13:33:14Z","timestamp":1631539994000},"page":"e1009384","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9745-8138","authenticated-orcid":true,"given":"Abhisek","family":"Dwivedy","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-6993","authenticated-orcid":true,"given":"Richard","family":"Mariadasse","sequence":"additional","affiliation":[]},{"given":"Mohammed","family":"Ahmad","sequence":"additional","affiliation":[]},{"given":"Sayan","family":"Chakraborty","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4692-4682","authenticated-orcid":true,"given":"Deepsikha","family":"Kar","sequence":"additional","affiliation":[]},{"given":"Satish","family":"Tiwari","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9087-8460","authenticated-orcid":true,"given":"Sankar","family":"Bhattacharyya","sequence":"additional","affiliation":[]},{"given":"Sudipta","family":"Sonar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8541-8315","authenticated-orcid":true,"given":"Shailendra","family":"Mani","sequence":"additional","affiliation":[]},{"given":"Prafullakumar","family":"Tailor","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1087-8493","authenticated-orcid":true,"given":"Tanmay","family":"Majumdar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-7592","authenticated-orcid":true,"given":"Jeyaraman","family":"Jeyakanthan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5927-3244","authenticated-orcid":true,"given":"Bichitra Kumar","family":"Biswal","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"pcbi.1009384.ref001","article-title":"RNA dependent RNA polymerases: Insights from structure, function and evolution","author":"S Venkataraman","year":"2018","journal-title":"Viruses"},{"key":"pcbi.1009384.ref002","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.virusres.2017.01.023","article-title":"Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes","author":"CC Posthuma","year":"2017","journal-title":"Virus Research"},{"key":"pcbi.1009384.ref003","doi-asserted-by":"crossref","first-page":"8416","DOI":"10.1093\/nar\/gkv838","article-title":"Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses","volume":"43","author":"KC Lehmann","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref004","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/bs.aivir.2016.08.008","article-title":"The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing","author":"EJ Snijder","year":"2016","journal-title":"Advances in Virus Research"},{"key":"pcbi.1009384.ref005","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-10280-3","article-title":"Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors","volume":"10","author":"RN Kirchdoerfer","year":"2019","journal-title":"Nat Commun"},{"key":"pcbi.1009384.ref006","article-title":"Structure of the RNA-dependent RNA polymerase from COVID-19 virus","author":"Y Gao","year":"2020","journal-title":"Science"},{"key":"pcbi.1009384.ref007","doi-asserted-by":"crossref","first-page":"8615","DOI":"10.1128\/JVI.75.18.8615-8623.2001","article-title":"Terminal Nucleotidyl Transferase Activity of Recombinant Flaviviridae RNA-Dependent RNA Polymerases: Implication for Viral RNA Synthesis","volume":"75","author":"CT Ranjith-Kumar","year":"2001","journal-title":"J Virol"},{"key":"pcbi.1009384.ref008","doi-asserted-by":"crossref","first-page":"35638","DOI":"10.1074\/jbc.M400460200","article-title":"A structural basis for the inhibition of the NS5 dengue virus mRNA 2\u2032-O-methyltransferase domain by ribavirin 5\u2032-triphosphate","volume":"279","author":"D Benarroch","year":"2004","journal-title":"J Biol Chem"},{"key":"pcbi.1009384.ref009","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1128\/JVI.02283-06","article-title":"Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution","volume":"81","author":"TL Yap","year":"2007","journal-title":"J Virol"},{"key":"pcbi.1009384.ref010","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1126\/science.1259210","article-title":"Structural basis for RNA replication by the hepatitis C virus polymerase","volume":"347","author":"TC Appleby","year":"2015","journal-title":"Science (80-)"},{"key":"pcbi.1009384.ref011","first-page":"57","article-title":"The coronavirus replicase","author":"J. Ziebuhr","year":"2005","journal-title":"Current Topics in Microbiology and Immunology"},{"key":"pcbi.1009384.ref012","article-title":"Nidovirus ribonucleases: Structures and functions in viral replication","author":"R Ulferts","year":"2011","journal-title":"RNA Biology"},{"key":"pcbi.1009384.ref013","article-title":"Coronavirus Disease 2019 (COVID-19): What we know?","author":"F He","year":"2020","journal-title":"J Med Virol"},{"key":"pcbi.1009384.ref014","first-page":"e00169","article-title":"Complete Genome Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Isolated in Nepal.","volume":"9","author":"R Sah","year":"2020","journal-title":"Microbiol Resour Announc"},{"key":"pcbi.1009384.ref015","article-title":"The proximal origin of SARS-CoV-2","author":"KG Andersen","year":"2020","journal-title":"Nat Med"},{"key":"pcbi.1009384.ref016","doi-asserted-by":"crossref","first-page":"m4857","DOI":"10.1136\/bmj.m4857","article-title":"Covid-19: New coronavirus variant is identified in UK","volume":"371","author":"J. Wise","year":"2020","journal-title":"BMJ"},{"key":"pcbi.1009384.ref017","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jmb.2017.12.007","article-title":"A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core","volume":"430","author":"L Zimmermann","year":"2018","journal-title":"J Mol Biol"},{"key":"pcbi.1009384.ref018","doi-asserted-by":"crossref","DOI":"10.1038\/srep28268","article-title":"ORION: A web server for protein fold recognition and structure prediction using evolutionary hybrid profiles","volume":"6","author":"Y Ghouzam","year":"2016","journal-title":"Sci Rep"},{"key":"pcbi.1009384.ref019","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.molcel.2004.08.024","article-title":"Regulation of protein kinases: Controlling activity through activation segment conformation","author":"B Nolen","year":"2004","journal-title":"Molecular Cell"},{"key":"pcbi.1009384.ref020","doi-asserted-by":"crossref","first-page":"6818","DOI":"10.1073\/pnas.1814279116","article-title":"Defining a new nomenclature for the structures of active and inactive kinases","volume":"116","author":"V Modi","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009384.ref021","doi-asserted-by":"crossref","first-page":"6361","DOI":"10.1073\/pnas.1816161116","article-title":"Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole","volume":"116","author":"T Beraki","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009384.ref022","first-page":"1","article-title":"Catalytic mechanisms and regulation of protein kinases","author":"Z Wang","year":"2014","journal-title":"Methods in Enzymology"},{"key":"pcbi.1009384.ref023","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/S0968-0004(02)02179-5","article-title":"Evolution of protein kinase signaling from yeast to man","author":"G Manning","year":"2002","journal-title":"Trends in Biochemical Sciences"},{"key":"pcbi.1009384.ref024","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification 1","volume":"9","author":"SK Hanks","year":"1995","journal-title":"FASEB J"},{"key":"pcbi.1009384.ref025","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1128\/JVI.01369-10","article-title":"Viral Serine\/Threonine Protein Kinases","volume":"85","author":"T Jacob","year":"2011","journal-title":"J Virol"},{"key":"pcbi.1009384.ref026","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1128\/MMBR.00027-06","article-title":"Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action","volume":"70","author":"MA Garcia","year":"2006","journal-title":"Microbiol Mol Biol Rev"},{"key":"pcbi.1009384.ref027","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.cell.2005.06.044","article-title":"Higher-order substrate recognition of eIF2\u03b1 by the RNA-dependent protein kinase PKR","volume":"122","author":"AC Dar","year":"2005","journal-title":"Cell"},{"key":"pcbi.1009384.ref028","article-title":"Comparative study of inhibition of drug potencies of c- Abl human kinase inhibitors: A computational and molecular docking study","volume":"2","author":"DK Dubey","year":"2010","journal-title":"J Biophys Struct Biol"},{"key":"pcbi.1009384.ref029","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.coviro.2017.04.003","article-title":"Biochemical principles and inhibitors to interfere with viral capping pathways","author":"E Decroly","year":"2017","journal-title":"Current Opinion in Virology"},{"key":"pcbi.1009384.ref030","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/S1097-2765(03)00187-4","article-title":"Structure of an mRNA capping enzyme bound to the phosphorylated carboxy-terminal domain of RNA polymerase II","volume":"11","author":"C Fabrega","year":"2003","journal-title":"Mol Cell"},{"key":"pcbi.1009384.ref031","doi-asserted-by":"crossref","first-page":"20172","DOI":"10.1073\/pnas.1113521108","article-title":"Genome-wide antisense transcription drives mRNA processing in bacteria","volume":"108","author":"I Lasa","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009384.ref032","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1128\/AAC.02675-15","article-title":"Synthetic \u03b1-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant Herpes simplex viruses","volume":"60","author":"PJ Ireland","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1009384.ref033","article-title":"Chemical Approaches to Inhibiting the Hepatitis B Virus Ribonuclease H","author":"JE Tavis","year":"2019","journal-title":"ACS Infect Dis"},{"key":"pcbi.1009384.ref034","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.antiviral.2017.04.012","article-title":"Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles","volume":"143","author":"TC Edwards","year":"2017","journal-title":"Antiviral Res"},{"key":"pcbi.1009384.ref035","doi-asserted-by":"crossref","first-page":"7451","DOI":"10.1128\/AAC.03875-14","article-title":"Inhibitors of nucleotidyltransferase superfamily enzymes suppress herpes simplex virus replication","volume":"58","author":"JE Tavis","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1009384.ref036","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.vetmic.2017.12.016","article-title":"Broad anti-herpesviral activity of \u03b1-hydroxytropolones","volume":"214","author":"SD Dehghanpir","year":"2018","journal-title":"Vet Microbiol"},{"key":"pcbi.1009384.ref037","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.antiviral.2018.01.015","article-title":"Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication","volume":"152","author":"Y Wang","year":"2018","journal-title":"Antiviral Res"},{"key":"pcbi.1009384.ref038","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1089\/mdr.2019.0144","article-title":"A Study of a Potent Inhibitor Against a GDP-6-Deoxy-\u03b1-d-Manno-Heptose Biosynthesis Pathway as Antibiotic Candidates","volume":"26","author":"S Kim","year":"2019","journal-title":"Microb Drug Resist"},{"key":"pcbi.1009384.ref039","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and drug-like compounds: The rule-of-five revolution","author":"CA Lipinski","year":"2004","journal-title":"Drug Discovery Today: Technologies"},{"key":"pcbi.1009384.ref040","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.bbapap.2005.07.036","article-title":"Substrate specificity of protein kinases and computational prediction of substrates","author":"B Kobe","year":"2005","journal-title":"Biochimica et Biophysica Acta\u2014Proteins and Proteomics"},{"key":"pcbi.1009384.ref041","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0009-2797(93)90108-B","article-title":"Studies of the potency of protein kinase inhibitors on ATPase activities","volume":"86","author":"JM Barret","year":"1993","journal-title":"Chem Biol Interact"},{"key":"pcbi.1009384.ref042","doi-asserted-by":"crossref","first-page":"33267","DOI":"10.1074\/jbc.M004748200","article-title":"Kinetic analysis of the cyclin-dependent kinase-activating kinase (Cak1p) from budding yeast","volume":"275","author":"DA Enke","year":"2000","journal-title":"J Biol Chem"},{"key":"pcbi.1009384.ref043","doi-asserted-by":"crossref","first-page":"5905","DOI":"10.1021\/bi00140a029","article-title":"The Intrinsic ATPase Activity of Protein Kinase C Is Catalyzed at the Active Site of the Enzyme","volume":"31","author":"NE Ward","year":"1992","journal-title":"Biochemistry"},{"key":"pcbi.1009384.ref044","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1177\/1087057106296047","article-title":"Three mechanistically distinct kinase assays compared: Measurement of intrinsic ATPase activity identified the most comprehensive set of ITK inhibitors","volume":"12","author":"MA Kashem","year":"2007","journal-title":"J Biomol Screen"},{"key":"pcbi.1009384.ref045","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.chembiol.2018.11.005","article-title":"What Makes a Kinase Promiscuous for Inhibitors?","volume":"26","author":"SM Hanson","year":"2019","journal-title":"Cell Chem Biol"},{"key":"pcbi.1009384.ref046","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/adt.2009.0222","article-title":"ADP-Glo: A bioluminescent and homogeneous adp monitoring assay for Kinases","volume":"7","author":"H Zegzouti","year":"2009","journal-title":"Assay Drug Dev Technol"},{"key":"pcbi.1009384.ref047","doi-asserted-by":"crossref","first-page":"13949","DOI":"10.1074\/jbc.M601384200","article-title":"Kinetic mechanism of AKT\/PKB enzyme family","volume":"281","author":"X Zhang","year":"2006","journal-title":"J Biol Chem"},{"key":"pcbi.1009384.ref048","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/0014-5793(92)81211-4","article-title":"ATP binding to bovine serum albumin","volume":"313","author":"M Bauer","year":"1992","journal-title":"FEBS Lett"},{"key":"pcbi.1009384.ref049","first-page":"584","article-title":"Structure of replicating SARS-CoV-2 polymerase","author":"HS Hillen","year":"2020","journal-title":"Nature"},{"key":"pcbi.1009384.ref050","first-page":"124","article-title":"Structural Basis of the Potential Binding Mechanism of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase","author":"L Zhang","year":"2020","journal-title":"J Phys Chem B"},{"key":"pcbi.1009384.ref051","volume-title":"WHO recommends against the use of remdesivir in COVID-19 patients","author":"World Health Organization","year":"2020"},{"key":"pcbi.1009384.ref052","first-page":"10","article-title":"Mutational hotspots and conserved domains of SARS-CoV-2 genome in African population.","author":"OE Omotoso","year":"2021","journal-title":"Beni-Suef Univ J Basic Appl Sci"},{"key":"pcbi.1009384.ref053","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-020-02344-6","article-title":"Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant","volume":"18","author":"M Pachetti","year":"2020","journal-title":"J Transl Med."},{"key":"pcbi.1009384.ref054","unstructured":"World Health Organization. Weekly epidemiological update on COVID-19\u201329 June 2021. 2021. Available: https:\/\/www.who.int\/publications\/m\/item\/weekly-epidemiological-update-on-covid-19\u201429-june-2021"},{"key":"pcbi.1009384.ref055","doi-asserted-by":"crossref","first-page":"2000058","DOI":"10.2807\/1560-7917.ES.2020.25.4.2000058","article-title":"Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020","volume":"25","author":"J Riou","year":"2020","journal-title":"Eurosurveillance."},{"key":"pcbi.1009384.ref056","article-title":"Genomic analysis of COVID-19 spread","author":"Sidney M. Bell","year":"2020","journal-title":"Situation report 2020-03-27"},{"key":"pcbi.1009384.ref057","doi-asserted-by":"crossref","DOI":"10.3332\/ecancer.2020.1022","article-title":"Associations between immune-suppressive and stimulating drugs and novel COVID-19\u2014a systematic review of current evidence","volume":"14","author":"B Russell","year":"2020","journal-title":"Ecancermedicalscience."},{"key":"pcbi.1009384.ref058","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.juro.2013.08.090","article-title":"Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules","volume":"191","author":"BJ Atkinson","year":"2014","journal-title":"J Urol"},{"key":"pcbi.1009384.ref059","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1158\/1535-7163.MCT-08-0013","article-title":"Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling","author":"SM Wilhelm","year":"2008","journal-title":"Molecular Cancer Therapeutics"},{"key":"pcbi.1009384.ref060","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.chembiol.2017.05.021","article-title":"Mechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib","volume":"24","author":"FA Ross","year":"2017","journal-title":"Cell Chem Biol"},{"key":"pcbi.1009384.ref061","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20070797","article-title":"The selectivity of protein kinase inhibitors: A further update","volume":"408","author":"J Bain","year":"2007","journal-title":"Biochem J"},{"key":"pcbi.1009384.ref062","doi-asserted-by":"crossref","first-page":"9018","DOI":"10.1128\/MCB.20.23.9018-9027.2000","article-title":"SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling","volume":"20","author":"RA Blake","year":"2000","journal-title":"Mol Cell Biol"},{"key":"pcbi.1009384.ref063","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s41429-019-0234-4","article-title":"Antiviral effect of sinefungin on in vitro growth of feline herpesvirus type 1","volume":"72","author":"Y Kuroda","year":"2019","journal-title":"J Antibiot (Tokyo)."},{"key":"pcbi.1009384.ref064","doi-asserted-by":"crossref","DOI":"10.1128\/mSystems.00416-19","article-title":"Genomewide Analysis of Mode of Action of the S-Adenosylmethionine Analogue Sinefungin in Leishmania infantum.","volume":"4","author":"A Bhattacharya","year":"2019","journal-title":"mSystems"},{"key":"pcbi.1009384.ref065","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1128\/AAC.00790-06","article-title":"Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5\u2032-triphosphate, not with inhibition of IMP dehydrogenase","volume":"51","author":"Y Sun","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1009384.ref066","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/liv.13212","article-title":"Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection","author":"JJ Feld","year":"2017","journal-title":"Liver International"},{"key":"pcbi.1009384.ref067","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007829","article-title":"Structure of a functional cap-binding domain in rift valley fever virus L protein","volume":"15","author":"N Gogrefe","year":"2019","journal-title":"PLoS Pathog"},{"key":"pcbi.1009384.ref068","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1107\/S2059798316000085","article-title":"The cap-binding site of influenza virus protein PB2 as a drug target","volume":"72","author":"C Severin","year":"2016","journal-title":"Acta Crystallogr Sect D Struct Biol"},{"key":"pcbi.1009384.ref069","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-24775-4","article-title":"A molecular dynamics simulation study decodes the Zika virus NS5 methyltransferase bound to SAH and RNA analogue","volume":"8","author":"CH Chuang","year":"2018","journal-title":"Sci Rep"},{"key":"pcbi.1009384.ref070","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2022310118","article-title":"Coronavirus replication-transcription complex: Vital and selective NMPylation of a conserved site in nsp9 by the NiRAN-RdRp subunit","volume":"118","author":"H Slanina","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009384.ref071","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.cell.2020.11.016","article-title":"Cryo-EM Structure of an Extended SARS-CoV-2 Replication and Transcription Complex Reveals an Intermediate State in Cap Synthesis","volume":"184","author":"L Yan","year":"2021","journal-title":"Cell"},{"key":"pcbi.1009384.ref072","first-page":"3.13.1","article-title":"Clustal Omega","volume":"2014","author":"F Sievers","year":"2014","journal-title":"Curr Protoc Bioinforma"},{"key":"pcbi.1009384.ref073","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1093\/bioinformatics\/9.5.614","article-title":"Multalin\u2013multiple sequence alignment","volume":"9","author":"C. Mitchell","year":"1993","journal-title":"Bioinformatics"},{"key":"pcbi.1009384.ref074","doi-asserted-by":"crossref","first-page":"c42","DOI":"10.1107\/S0108767305098211","article-title":"ESPript\/ENDscript: sequence and 3D information from protein structures","volume":"61","author":"P Gouet","year":"2005","journal-title":"Acta Crystallogr Sect A Found Crystallogr"},{"key":"pcbi.1009384.ref075","doi-asserted-by":"crossref","first-page":"W351","DOI":"10.1093\/nar\/gkw357","article-title":"Dali server update","volume":"44","author":"L Holm","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref076","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1093\/bioinformatics\/btv462","article-title":"Improving protein fold recognition with hybrid profiles combining sequence and structure evolution","volume":"31","author":"Y Ghouzam","year":"2015","journal-title":"Bioinformatics"},{"key":"pcbi.1009384.ref077","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1110\/ps.03602304","article-title":"Database searching by flexible protein structure alignment","volume":"13","author":"Y Ye","year":"2004","journal-title":"Protein Sci"},{"key":"pcbi.1009384.ref078","article-title":"The PyMOL Molecular Graphics System","author":"WL DeLano","year":"2002","journal-title":"Schr\u00f6dinger LLC wwwpymolorg"},{"key":"pcbi.1009384.ref079","doi-asserted-by":"crossref","first-page":"D428","DOI":"10.1093\/nar\/gkx1077","article-title":"The eukaryotic linear motif resource\u20142018 update","volume":"46","author":"M Gouw","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref080","doi-asserted-by":"crossref","first-page":"W402","DOI":"10.1093\/nar\/gkz297","article-title":"The PSIPRED Protein Analysis Workbench: 20 years on","volume":"47","author":"DWA Buchan","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref081","doi-asserted-by":"crossref","first-page":"D222","DOI":"10.1093\/nar\/gku1221","article-title":"CDD: NCBI\u2019s conserved domain database","volume":"43","author":"A Marchler-Bauer","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref082","first-page":"35","article-title":"MyHits: Improvements to an interactive resource for analyzing protein sequences","author":"M Pagni","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref083","first-page":"7","article-title":"PhosphoPredict: A bioinformatics tool for prediction of human kinase-specific phosphorylation substrates and sites by integrating heterogeneous feature selection","author":"J Song","year":"2017","journal-title":"Sci Rep"},{"key":"pcbi.1009384.ref084","volume-title":"Schr\u00f6dinger Release 2019\u20133: Glide","author":"U. Manual","year":"2019"},{"key":"pcbi.1009384.ref085","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"LA Kelley","year":"2015","journal-title":"Nat Protoc"},{"key":"pcbi.1009384.ref086","doi-asserted-by":"crossref","first-page":"W363","DOI":"10.1093\/nar\/gky473","article-title":"CASTp 3.0: Computed atlas of surface topography of proteins","volume":"46","author":"W Tian","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009384.ref087","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1021\/acs.jcim.6b00196","article-title":"Improved Computation of Protein-Protein Relative Binding Energies with the Nwat-MMGBSA Method","volume":"56","author":"I Maffucci","year":"2016","journal-title":"J Chem Inf Model"},{"key":"pcbi.1009384.ref088","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1021\/acs.jcim.9b00755","article-title":"Insights into Exogenous Tryptophan-Mediated Allosteric Communication and Helical Transition of TRP Protein for Transcription Regulation","volume":"60","author":"R Mariadasse","year":"2020","journal-title":"J Chem Inf Model"},{"key":"pcbi.1009384.ref089","first-page":"181","article-title":"Molecular Docking, Molecular Dynamics Simulations, Computational Screening to Design Quorum Sensing Inhibitors Targeting LuxP of Vibrio harveyi and Its Biological Evaluation","author":"S Rajamanikandan","year":"2017","journal-title":"Appl Biochem Biotechnol"},{"key":"pcbi.1009384.ref090","article-title":"Predicting ADME properties in silico: Methods and models","author":"D Butina","year":"2002","journal-title":"Drug Discovery Today"},{"key":"pcbi.1009384.ref091","first-page":"583","article-title":"Investigation of vital pathogenic target orotate phosphoribosyltransferases (OPRTase) from Thermus thermophilus HB8: Phylogenetic and molecular modeling approach","author":"K Surekha","year":"2016","journal-title":"Gene"},{"key":"pcbi.1009384.ref092","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0199348","article-title":"Construction of an integrated database for hERG blocking small molecules","volume":"13","author":"T Sato","year":"2018","journal-title":"PLoS One"},{"key":"pcbi.1009384.ref093","doi-asserted-by":"crossref","DOI":"10.1186\/1472-6750-9-61","article-title":"Simple and efficient site-directed mutagenesis using two single-primer reactions in parallel to generate mutants for protein structure-function studies","volume":"9","author":"O Edelheit","year":"2009","journal-title":"BMC Biotechnol"},{"key":"pcbi.1009384.ref094","doi-asserted-by":"crossref","DOI":"10.1016\/j.jprot.2020.103669","article-title":"Comparative evaluation of label-free quantification strategies","volume":"215","author":"L Zhao","year":"2020","journal-title":"J Proteomics"},{"key":"pcbi.1009384.ref095","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s12250-020-00241-2","article-title":"Isolation and Growth Characteristics of SARS-CoV-2 in Vero Cell","author":"P Yao","year":"2020","journal-title":"Virologica Sinica"},{"key":"pcbi.1009384.ref096","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.3201\/eid2608.201246","article-title":"US CDC real-time reverse transcription PCR panel for detection of severe acute respiratory syndrome Coronavirus 2","volume":"26","author":"X Lu","year":"2020","journal-title":"Emerg Infect Dis"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009384","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009384","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T13:59:50Z","timestamp":1699451990000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009384"}},"subtitle":[],"editor":[{"given":"Avner","family":"Schlessinger","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2021,9,13]]},"references-count":96,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009384","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.02.03.429510","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,13]]}}}