{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:22:20Z","timestamp":1789906940468,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Piattaforma NoCovid@UMG Progetto POR Calabria-FESR\/FSE 2014-2020- Azione 10.5.12","award":["DDRC n. 4584 del 4\/5\/2021"],"award-info":[{"award-number":["DDRC n. 4584 del 4\/5\/2021"]}]},{"name":"Piattaforma NoCovid@UMG Progetto POR Calabria-FESR\/FSE 2014-2020- Azione 10.5.12","award":["FISR2020IP_04758"],"award-info":[{"award-number":["FISR2020IP_04758"]}]},{"name":"Fondo integrativo speciale per la ricerca","award":["DDRC n. 4584 del 4\/5\/2021"],"award-info":[{"award-number":["DDRC n. 4584 del 4\/5\/2021"]}]},{"name":"Fondo integrativo speciale per la ricerca","award":["FISR2020IP_04758"],"award-info":[{"award-number":["FISR2020IP_04758"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5\u2032 to 3\u2032 direction and acts in concert with the replication\u2013transcription complex (nsp7\/nsp8\/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme\u2019s binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.<\/jats:p>","DOI":"10.3390\/molecules27217522","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T04:00:51Z","timestamp":1667534451000},"page":"7522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Targeting SARS-CoV-2 nsp13 Helicase and Assessment of Druggability Pockets: Identification of Two Potent Inhibitors by a Multi-Site In Silico Drug Repurposing Approach"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5799-7863","authenticated-orcid":false,"given":"Isabella","family":"Romeo","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4874-2946","authenticated-orcid":false,"given":"Francesca Alessandra","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-9479","authenticated-orcid":false,"given":"Giosu\u00e8","family":"Costa","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-8636","authenticated-orcid":false,"given":"Angela","family":"Corona","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0085-8990","authenticated-orcid":false,"given":"Mohammad","family":"Alkhatib","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Salpini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Lemme","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3227-5765","authenticated-orcid":false,"given":"Davide","family":"Vergni","sequence":"additional","affiliation":[{"name":"Istituto per le Applicazioni del Calcolo \u201cMauro Picone\u201d-CNR, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Svicher","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6228-1114","authenticated-orcid":false,"given":"Maria Mercedes","family":"Santoro","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-0980","authenticated-orcid":false,"given":"Enzo","family":"Tramontano","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ceccherini-Silberstein","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 Tor Vergata di Roma, Via Montpellier, 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Artese","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, Universit\u00e0 degli Studi \u201cMagna Gr\u00e6cia\u201d di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref_1","unstructured":"(2022, September 16). WHO COVID-19 Dashboard. Available online: https:\/\/covid19.who.int\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e61312","DOI":"10.7554\/eLife.61312","article-title":"Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants","volume":"9","author":"Weisblum","year":"2020","journal-title":"Elife"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/S1473-3099(20)30764-7","article-title":"Genomic evidence for reinfection with SARS-CoV-2: A case study","volume":"21","author":"Tillett","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41577-020-00480-0","article-title":"Viral targets for vaccines against COVID-19","volume":"21","author":"Dai","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2020.07.012","article-title":"The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity","volume":"182","author":"Li","year":"2020","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijbiomac.2021.02.071","article-title":"Potential drug targets of SARS-CoV-2: From genomics to therapeutics","volume":"177","author":"Shamsi","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"BSR20201256","DOI":"10.1042\/BSR20201256","article-title":"Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: Possible implication in COVID-19 therapy","volume":"40","author":"Shamsi","year":"2020","journal-title":"Biosci Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Imran, M., Kumar Arora, M., Asdaq, S.M.B., Khan, S.A., Alaqel, S.I., Alshammari, M.K., Alshehri, M.M., Alshrari, A.S., Mateq Ali, A., and Al-shammeri, A.M. (2021). Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19. Molecules, 26.","DOI":"10.3390\/molecules26195795"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.jiph.2020.10.012","article-title":"Combating COVID-19: The role of drug repurposing and medicinal plants","volume":"14","author":"Khan","year":"2021","journal-title":"J. Infect. Public Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.jiph.2021.06.013","article-title":"Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review","volume":"14","author":"Imran","year":"2021","journal-title":"J. Infect. Public Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1055\/a-1296-7935","article-title":"Favipiravir and COVID-19: A Simplified Summary","volume":"71","author":"Pashapour","year":"2021","journal-title":"Drug Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaax5866","DOI":"10.1126\/scitranslmed.aax5866","article-title":"Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia","volume":"11","author":"Toots","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eabo0718","DOI":"10.1126\/scitranslmed.abo0718","article-title":"Mutations in the SARS-CoV-2 RNA dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms","volume":"14","author":"Stevens","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41594-021-00651-0","article-title":"Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis","volume":"28","author":"Kabinger","year":"2021","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s41392-021-00837-4","article-title":"A novel model of molnupiravir against SARS-CoV-2 replication: Accumulated RNA mutations to induce error catastrophe","volume":"6","author":"Zhao","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100770","DOI":"10.1016\/j.jbc.2021.100770","article-title":"Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template","volume":"297","author":"Gordon","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e0273221","DOI":"10.1128\/spectrum.02732-21","article-title":"Update on SARS-CoV-2 Omicron Variant of Concern and Its Peculiar Mutational Profile","volume":"10","author":"Alkhatib","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1093\/jac\/dkaa444","article-title":"Key genetic elements, single and in clusters, underlying geographically dependent SARS-CoV-2 genetic adaptation and their impact on binding affinity for drugs and immune control","volume":"76","author":"Salpini","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1016\/j.cell.2020.07.033","article-title":"Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex","volume":"182","author":"Chen","year":"2020","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5874","DOI":"10.1038\/s41467-020-19770-1","article-title":"Architecture of a SARS-CoV-2 mini replication and transcription complex","volume":"11","author":"Yan","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5619","DOI":"10.1128\/JVI.78.11.5619-5632.2004","article-title":"Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase","volume":"78","author":"Ivanov","year":"2004","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1021\/jm00145a002","article-title":"A computational procedure for determining energetically favorable binding sites on biologically important macromolecules","volume":"28","author":"Goodford","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.1038\/s41467-021-25166-6","article-title":"Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase","volume":"12","author":"Newman","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.bbrc.2022.02.068","article-title":"The stalk domain of SARS-CoV-2 NSP13 is essential for its helicase activity","volume":"601","author":"Yue","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1142\/S0219633602000117","article-title":"Protein structure: Insights from graph theory","volume":"1","author":"Vishveshwara","year":"2002","journal-title":"J. Theor. Comput. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1021\/acs.jmedchem.0c02227","article-title":"Decision Making in Structure-Based Drug Discovery: Visual Inspection of Docking Results","volume":"64","author":"Fischer","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1592\/phco.30.4.375","article-title":"Ceftaroline: A new cephalosporin with activity against resistant gram-positive pathogens","volume":"30","author":"Steed","year":"2010","journal-title":"Pharmacotherapy"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0955-0674(03)00006-1","article-title":"Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease","volume":"15","author":"Lin","year":"2003","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.3109\/13880209.2013.792849","article-title":"Polydatin: A review of pharmacology and pharmacokinetics","volume":"51","author":"Du","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s40262-013-0048-7","article-title":"Characterizing systemic exposure of inhaled drugs: Application to the long-acting \u03b22-agonist PF-00610355","volume":"52","author":"Diderichsen","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1517\/13543784.2015.1006358","article-title":"Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease","volume":"24","author":"Norman","year":"2015","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1128\/AAC.00957-12","article-title":"Severe acute respiratory syndrome coronavirus replication inhibitor that interferes with the nucleic acid unwinding of the viral helicase","volume":"56","author":"Adedeji","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1021\/acsptsci.1c00253","article-title":"Natural Compounds Inhibit SARS-CoV-2 nsp13 Unwinding and ATPase Enzyme Activities","volume":"5","author":"Corona","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_35","first-page":"57","article-title":"The coronavirus replicase","volume":"287","author":"Ziebuhr","year":"2005","journal-title":"Curr. Top Microbiol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1021\/acs.jproteome.1c00206","article-title":"Genetic Variability of the SARS-CoV-2 Pocketome","volume":"20","author":"Yazdani","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12725","DOI":"10.1021\/acs.jmedchem.0c01063","article-title":"Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19","volume":"63","author":"Hoffman","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yang, H., Xie, W., Xue, X., Yang, K., Ma, J., Liang, W., Zhao, Q., Zhou, Z., Pei, D., and Ziebuhr, J. (2005). Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol., 3.","DOI":"10.1371\/journal.pbio.0030428"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107930","DOI":"10.1016\/j.pharmthera.2021.107930","article-title":"Drug repurposing for COVID-19: Approaches, challenges and promising candidates","volume":"228","author":"Ng","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e02428-20","DOI":"10.1128\/AAC.02428-20","article-title":"Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2","volume":"65","author":"Painter","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"100721","DOI":"10.1016\/j.drup.2020.100721","article-title":"Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses","volume":"53","author":"Artese","year":"2020","journal-title":"Drug Resist. Updates"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1016\/j.sjbs.2021.02.059","article-title":"Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19","volume":"28","author":"Sharma","year":"2021","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.yjmcc.2020.05.007","article-title":"p38 MAPK inhibition: A promising therapeutic approach for COVID-19","volume":"144","author":"Grimes","year":"2020","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_46","unstructured":"(2018). Protein Preparation Wizard, Schr\u00f6dinger, LLC."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_48","unstructured":"(2020, October 01). Available online: www.drugbank.ca."},{"key":"ref_49","unstructured":"(2018). LigPrep, Schr\u00f6dinger, LLC."},{"key":"ref_50","unstructured":"(2018). MacroModel, Schr\u00f6dinger, LLC."},{"key":"ref_51","unstructured":"(2018). Glide, Schr\u00f6dinger, LLC."},{"key":"ref_52","unstructured":"(2018). Maestro, Schr\u00f6dinger, LLC."},{"key":"ref_53","unstructured":"(The PyMOL Molecular Graphics System, 2015). The PyMOL Molecular Graphics System, Version 2.0."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1006\/jmbi.1999.3058","article-title":"Identification of side-chain clusters in protein structures by a graph spectral method","volume":"292","author":"Kannan","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/bioinformatics\/btx586","article-title":"RINspector: A Cytoscape app for centrality analyses and DynaMine flexibility prediction","volume":"34","author":"Brysbaert","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"684970","DOI":"10.3389\/fbinf.2021.684970","article-title":"Centrality Measures in Residue Interaction Networks to Highlight Amino Acids in Protein-Protein Binding","volume":"1","author":"Brysbaert","year":"2021","journal-title":"Front. Bioinform."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2006.0019","DOI":"10.1038\/msb4100063","article-title":"Residues crucial for maintaining short paths in network communication mediate signaling in proteins","volume":"2","author":"Fujihashi","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0169-7161(07)27004-X","article-title":"4 statistical methods for assessing biomarkers and analyzing biomarker data","volume":"27","author":"Looney","year":"2007","journal-title":"Handb. Stat."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"10290","DOI":"10.1038\/s41598-021-89724-0","article-title":"Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase","volume":"11","author":"Abidi","year":"2021","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7522\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:10:01Z","timestamp":1760145001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":59,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27217522"],"URL":"https:\/\/doi.org\/10.3390\/molecules27217522","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]}}}