{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:00:28Z","timestamp":1782450028717,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research, Taif university, Taif, KSA","award":["1-443-2"],"award-info":[{"award-number":["1-443-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The severe acute respiratory syndrome coronavirus 2, also known as SARS-CoV-2, is the causative agent of the COVID-19 global pandemic. SARS-CoV-2 has a highly conserved non-structural protein 12 (NSP-12) involved in RNA-dependent RNA polymerase (RdRp) activity. For the identification of potential inhibitors for NSP-12, computational approaches such as the identification of homologous proteins that have been previously targeted by FDA-approved antivirals can be employed. Herein, homologous proteins of NSP-12 were retrieved from Protein DataBank (PDB) and the evolutionary conserved sequence and structure similarity of the active site of the RdRp domain of NSP-12 was characterized. The identified homologous structures of NSP-12 belonged to four viral families: Coronaviridae, Flaviviridae, Picornaviridae, and Caliciviridae, and shared evolutionary conserved relationships. The multiple sequences and structural alignment of homologous structures showed highly conserved amino acid residues that were located at the active site of the RdRp domain of NSP-12. The conserved active site of the RdRp domain of NSP-12 was evaluated for binding affinity with the FDA-approved antivirals, i.e., Sofosbuvir and Dasabuvir in a molecular docking study. The molecular docking of Sofosbuvir and Dasabuvir with the active site that contains conserved motifs (motif A-G) of the RdRp domain of NSP-12 revealed significant binding affinity. Furthermore, MD simulation also inferred the potency of Sofosbuvir and Dasabuvir. In conclusion, targeting the active site of the RdRp domain of NSP-12 with Dasabuvir and Sofosbuvir might reduce viral replication and pathogenicity and could be further studied for the treatment of SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/molecules27227732","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T21:33:02Z","timestamp":1668115982000},"page":"7732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Structural Homology-Based Drug Repurposing Approach for Targeting NSP12 SARS-CoV-2"],"prefix":"10.3390","volume":"27","author":[{"given":"Abdulelah","family":"Aljuaid","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-4282","authenticated-orcid":false,"given":"Abdus","family":"Salam","sequence":"additional","affiliation":[{"name":"Precision Medicine Lab, Laboratory Building, Rehman Medical Institute, Phase-V, Hayatabad, Peshawar 25000, Khyber Pakhtunkhwa, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-8667","authenticated-orcid":false,"given":"Mazen","family":"Almehmadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soukayna","family":"Baammi","sequence":"additional","affiliation":[{"name":"African Genome Centre (AGC), Mohammed VI Polytechnic University, Benguerir 43150, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5827-6040","authenticated-orcid":false,"given":"Fahad M.","family":"Alshabrmi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-7748","authenticated-orcid":false,"given":"Mamdouh","family":"Allahyani","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadijah M.","family":"Al-Zaydi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, University of Jeddah, Jeddah 23738, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4769-2177","authenticated-orcid":false,"given":"Abdullah M.","family":"Izmirly","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"},{"name":"Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center and Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7449-4651","authenticated-orcid":false,"given":"Sarah","family":"Almaghrabi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"},{"name":"Center of Innovations in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3866-6935","authenticated-orcid":false,"given":"Bandar K.","family":"Baothman","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Shahab","sequence":"additional","affiliation":[{"name":"State Key Laboratories of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1039\/C5MB00306G","article-title":"Protein localization vector propagation: A method for improving the accuracy of drug repositioning","volume":"11","author":"Yeu","year":"2015","journal-title":"Mol. BioSyst."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/534314a","article-title":"Can you teach old drugs new tricks?","volume":"534","author":"Nosengo","year":"2016","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","unstructured":"(2020, May 07). WHO. Available online: https:\/\/www.who.int\/news-room\/detail\/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov)."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"McKibbin, W., and Fernando, R. (2020). The Global Macroeconomic Impacts of COVID-19: Seven Scenarios, SSRN. CAMA Working Paper No. 19\/2020.","DOI":"10.2139\/ssrn.3547729"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ijsu.2020.02.034","article-title":"World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19)","volume":"76","author":"Sohrabi","year":"2020","journal-title":"Int. J. Surg."},{"key":"ref_7","unstructured":"(2020, May 29). WHO. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1001\/jama.2020.0757","article-title":"Coronavirus infections\u2014More than just the common cold","volume":"323","author":"Paules","year":"2020","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.1128\/JVI.77.16.8801-8811.2003","article-title":"The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex","volume":"77","author":"Bosch","year":"2003","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5927","DOI":"10.1128\/JVI.02501-05","article-title":"Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex","volume":"80","author":"Snijder","year":"2006","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Brian, D., and Baric, R. (2005). Coronavirus genome structure and replication. Coronavirus Replication and Reverse Genetics, Springer.","DOI":"10.1007\/3-540-26765-4_1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/jmv.25681","article-title":"Emerging coronaviruses: Genome structure, replication, and pathogenesis","volume":"92","author":"Chen","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2342","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":"Kirchdoerfer","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_15","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":"Lehmann","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/978-3-540-75157-1_7","article-title":"Structure-function relationships among RNA-dependent RNA polymerases","volume":"320","author":"Ng","year":"2008","journal-title":"RNA Interf."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Choi, K.H. (2012). Viral polymerases. Viral Molecular Machines, Springer.","DOI":"10.1007\/978-1-4614-0980-9_12"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105933","DOI":"10.1016\/j.ijantimicag.2020.105933","article-title":"Arguments in favour of remdesivir for treating SARS-CoV-2 infections","volume":"55","author":"Ko","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/jmv.26222","article-title":"SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12)","volume":"93","author":"Ruan","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41401-021-00668-7","article-title":"A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors","volume":"43","author":"Ren","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/07391102.2020.1813628","article-title":"Potential inhibitors of SARS-CoV-2 RNA dependent RNA polymerase protein: Molecular docking, molecular dynamics simulations and MM-PBSA analyses","volume":"40","author":"Elkarhat","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ymeth.2021.02.017","article-title":"Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies","volume":"195","author":"Kumar","year":"2021","journal-title":"Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s13205-020-02610-w","article-title":"Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: An in silico approach","volume":"11","author":"Singh","year":"2021","journal-title":"3 Biotech"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.2174\/1574887109666140529222602","article-title":"Dasabuvir: A non-nucleoside inhibitor of NS5B for the treatment of hepatitis C virus infection","volume":"9","author":"Gentile","year":"2014","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/bs.enz.2021.06.003","article-title":"HCV RdRp, sofosbuvir and beyond","volume":"49","author":"Feng","year":"2021","journal-title":"Enzymes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/35065653","article-title":"A mechanism for initiating RNA-dependent RNA polymerization","volume":"410","author":"Butcher","year":"2001","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22505","DOI":"10.1073\/pnas.1007626107","article-title":"Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase","volume":"107","author":"Gong","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0022-2836(02)01033-1","article-title":"The Palm Subdomain-based Active Site is Internally Permuted in Viral RNA-dependent RNA Polymerases of an Ancient Lineage","volume":"324","author":"Pringle","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1517\/17460441.1.3.261","article-title":"Pharmacophore modelling: Applications in drug discovery","volume":"1","author":"Langer","year":"2006","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1056\/NEJMoa2007016","article-title":"Compassionate Use of Remdesivir for Patients with Severe COVID-19","volume":"382","author":"Grein","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"197867","DOI":"10.1016\/j.virusres.2020.197867","article-title":"Structural insights into NS5B protein of novel equine hepaciviruses and pegiviruses complexed with polymerase inhibitors","volume":"278","author":"Santos","year":"2020","journal-title":"Virus Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Venkataraman, S., Prasad, B.V.L.S., and Selvarajan, R. (2018). RNA dependent RNA polymerases: Insights from structure, function and evolution. Viruses, 10.","DOI":"10.3390\/v10020076"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.3389\/fmicb.2019.01945","article-title":"A structure-function diversity survey of the RNA-dependent RNA polymerases from the positive-strand RNA viruses","volume":"10","author":"Jia","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E4005","DOI":"10.1073\/pnas.1602591113","article-title":"Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation","volume":"113","author":"Shu","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1126\/science.abb7498","article-title":"Structure of the RNA-dependent RNA polymerase from COVID-19 virus","volume":"368","author":"Gao","year":"2020","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W545","DOI":"10.1093\/nar\/gkq366","article-title":"Dali server: Conservation mapping in 3D","volume":"38","author":"Holm","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W351","DOI":"10.1093\/nar\/gkw357","article-title":"Dali server update","volume":"44","author":"Holm","year":"2016","journal-title":"Nucliec Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/pro.3749","article-title":"DALI and the persistence of protein shape","volume":"29","author":"Holm","year":"2020","journal-title":"Protein Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/nar\/gkn072","article-title":"PROMALS3D: A tool for multiple protein sequence and structure alignments","volume":"36","author":"Pei","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera?A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"W374","DOI":"10.1093\/nar\/gky380","article-title":"CavityPlus: A web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction","volume":"46","author":"Xu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.2174\/1381612811319120019","article-title":"Binding site detection and druggability prediction of protein targets for structure-based drug design","volume":"19","author":"Yuan","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_44","unstructured":"Oliveros, J.C. (2020, May 13). VENNY. An Interactive Tool for Comparing Lists with Venn Diagrams. Available online: http:\/\/bioinfogp.cnb.csic.es\/tools\/venny\/index.html."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nprot.2016.051","article-title":"Computational protein\u2013ligand docking and virtual drug screening with the AutoDock suite","volume":"11","author":"Forli","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/978-1-4939-2343-4_27","article-title":"Scoring functions for AutoDock","volume":"1273","author":"Hill","year":"2015","journal-title":"Glycoinformatics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/7732\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:13:50Z","timestamp":1760145230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/22\/7732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":49,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27227732"],"URL":"https:\/\/doi.org\/10.3390\/molecules27227732","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}