{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T08:57:08Z","timestamp":1778057828564,"version":"3.51.4"},"reference-count":126,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T00:00:00Z","timestamp":1613779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/17\/45\/33071"],"award-info":[{"award-number":["PG\/17\/45\/33071"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002\u20132004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.<\/jats:p>","DOI":"10.3390\/molecules26041134","type":"journal-article","created":{"date-parts":[[2021,2,21]],"date-time":"2021-02-21T22:04:15Z","timestamp":1613945055000},"page":"1134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease"],"prefix":"10.3390","volume":"26","author":[{"given":"Roxanna","family":"Hajbabaie","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Cambridge University, Tennis Court Road, Cambridge CB2 1PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew T.","family":"Harper","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cambridge University, Tennis Court Road, Cambridge CB2 1PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3830-5160","authenticated-orcid":false,"given":"Taufiq","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Cambridge University, Tennis Court Road, Cambridge CB2 1PD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2021, January 03). Coronavirus Disease (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/s41591-020-0863-y","article-title":"If the world fails to protect the economy, COVID-19 will damage health not just now but also in the future","volume":"26","author":"McKee","year":"2020","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ijsu.2020.04.018","article-title":"The socio-economic implications of the coronavirus pandemic (COVID-19): A review","volume":"78","author":"Nicola","year":"2020","journal-title":"Int. J. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Saladino, V., Algeri, D., and Auriemma, V. (2020). The Psychological and Social Impact of Covid-19: New Perspectives of Well-Being. Front. Psychol., 11.","DOI":"10.3389\/fpsyg.2020.577684"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/S0140-6736(20)30460-8","article-title":"The psychological impact of quarantine and how to reduce it: Rapid review of the evidence","volume":"395","author":"Brooks","year":"2020","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/s41564-020-0695-z","article-title":"The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"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","unstructured":"Hu, B., Guo, H., Zhou, P., and Shi, Z.-L. (2020). Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol.","DOI":"10.1038\/s41579-020-00459-7"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0140-6736(20)32651-9","article-title":"Infectivity of asymptomatic versus symptomatic COVID-19","volume":"397","author":"Sayampanathan","year":"2021","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1136\/bmj.m4851","article-title":"Asymptomatic transmission of covid-19","volume":"371","author":"Pollock","year":"2020","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1056\/NEJMcp2009575","article-title":"Severe Covid-19","volume":"383","author":"Berlin","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xu, G., and Huang, Y.W. (2020). Modeling the load of SARS-CoV-2 virus in human expelled particles during coughing and speaking. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241539"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/s41591-020-0916-2","article-title":"Real-time tracking of self-reported symptoms to predict potential COVID-19","volume":"26","author":"Menni","year":"2020","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/S1473-3099(20)30484-9","article-title":"Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics","volume":"20","author":"Petersen","year":"2020","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mahase, E. (2020). Coronavirus: Covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ, 368.","DOI":"10.1136\/bmj.m641"},{"key":"ref_17","unstructured":"World Health Organization (WHO) (2015). Blueprint for R&D Preparedness and Response to Public Health Emergencies due to Highly Infectious Pathogens, WHO."},{"key":"ref_18","unstructured":"US Food and Drug Administration (2021, January 03). Approval of Pfizer-BioNTech COVID-19 Vaccine, Available online: https:\/\/www.fda.gov\/emergency-preparedness-and-response\/coronavirus-disease-2019-covid-19\/pfizer-biontech-covid-19-vaccine."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_20","unstructured":"US Food and Drug Administration (2021, January 08). Moderna COVID-19 Vaccine, Available online: https:\/\/www.fda.gov\/emergency-preparedness-and-response\/coronavirus-disease-2019-covid-19\/moderna-covid-19-vaccine."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1056\/NEJMoa2022483","article-title":"An mRNA Vaccine against SARS-CoV-2\u2014Preliminary Report","volume":"383","author":"Jackson","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_22","unstructured":"UK Government (2021, January 08). Oxford University\/AstraZeneca COVID-19 Vaccine Approved, Available online: https:\/\/www.gov.uk\/government\/news\/oxford-universityastrazeneca-covid-19-vaccine-approved."},{"key":"ref_23","unstructured":"AstraZeneca (2021, January 08). AstraZeneca\u2019s COVID-19 Vaccine Authorised for Emergency Supply in the UK. Available online: https:\/\/www.astrazeneca.com\/media-centre\/press-releases\/2020\/astrazenecas-covid-19-vaccine-authorised-in-uk.html."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0140-6736(20)32623-4","article-title":"Oxford-AstraZeneca COVID-19 vaccine efficacy","volume":"397","author":"Knoll","year":"2021","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Logunov, D.Y., Dolzhikova, I.V., Shcheblyakov, D.V., Tukhvatulin, A.I., Zubkova, O.V., Dzharullaeva, A.S., Kovyrshina, A.V., Lubenets, N.L., Grousova, D.M., and Erokhova, A.S. (2021). Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: An interim analysis of a randomised controlled phase 3 trial in Russia. Lancet.","DOI":"10.1016\/S0140-6736(21)00234-8"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1473-3099(20)30843-4","article-title":"Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18\u201359 years: A randomised, double-blind, placebo-controlled, phase 1\/2 clinical trial","volume":"21","author":"Zhang","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Augustin, T.L., Hajbabaie, R., Harper, M.T., and Rahman, T. (2020). Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach. Molecules, 25.","DOI":"10.3390\/molecules25235501"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.1038\/s41467-020-18709-w","article-title":"Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease","volume":"11","author":"Douangamath","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","unstructured":"US Food and Drug Administration (2021, January 03). Approval of Veklury (remdesivir) for the Treatment of COVID-19\u2014The Science of Safety and Effectiveness, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-treatment-covid-19."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1126\/science.abc1560","article-title":"Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir","volume":"368","author":"Yin","year":"2020","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Martinot, M., Jary, A., Fafi-Kremer, S., Leducq, V., Delagreverie, H., Garnier, M., Pacanowski, J., M\u00e9kinian, A., Pirenne, F., and Tiberghien, P. (2020). Remdesivir failure with SARS-CoV-2 RNA-dependent RNA-polymerase mutation in a B-cell immunodeficient patient with protracted Covid-19. Clin. Infect. Dis.","DOI":"10.1093\/cid\/ciaa1474"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Young, B., Tan, T.T., and Leo, Y.S. (2020). The place for remdesivir in COVID-19 treatment. Lancet.","DOI":"10.1016\/S1473-3099(20)30911-7"},{"key":"ref_33","unstructured":"World Health Organization (WHO) (2021, January 02). Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19\u2014Interim WHO Solidarity Trial Results. Available online: https:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa2023184."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.1136\/bmj.m4120","article-title":"Covid-19: US approves remdesivir despite WHO trial showing lack of efficacy","volume":"371","author":"Mahase","year":"2020","journal-title":"BMJ"},{"key":"ref_36","unstructured":"Faccenda, E., Armstrong, J.F., Davenport, A.P., Harding, S.D., Pawson, A.J., Southan, C., and Davies, J.A. (2021, January 02). Coronavirus Information. IUPHAR\/BPS Guide to Pharmacology. Available online: https:\/\/www.guidetopharmacology.org\/coronavirus.jsp."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Alexander, S.P., Ball, J.K., and Tsoleridis, T. (2020). SARS-CoV-2 proteins (version 2020.2) in the IUPHAR\/BPS Guide to Pharmacology Database. IUPHAR\/BPS Guide Pharmacol. Cite, 2020.","DOI":"10.2218\/gtopdb\/F1034\/2020.2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1021\/acsinfecdis.0c00168","article-title":"Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease","volume":"6","author":"Freitas","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"W\u0119glarz-Tomczak, E., Tomczak, J.M., Talma, M., and Brul, S. (2020). Ebselen as a highly active inhibitor of PLPro CoV2. BioRxiv.","DOI":"10.1101\/2020.05.17.100768"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41467-020-20718-8","article-title":"The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery","volume":"12","author":"Fu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16119","DOI":"10.1073\/pnas.0805240105","article-title":"A noncovalent class of papain-like protease\/deubiquitinase inhibitors blocks SARS virus replication","volume":"105","author":"Ratia","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eabd4596","DOI":"10.1126\/sciadv.abd4596","article-title":"Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design","volume":"6","author":"Rut","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41392-020-00335-z","article-title":"SARS-CoV-2: The many pros of targeting PLpro","volume":"5","author":"McClain","year":"2020","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.toxrep.2018.08.017","article-title":"The use of structural alerts to avoid the toxicity of pharmaceuticals","volume":"5","author":"Limban","year":"2018","journal-title":"Toxicol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"438","DOI":"10.2174\/0929867321666141112122118","article-title":"Should the incorporation of structural alerts be restricted in drug design? An analysis of structure-toxicity trends with aniline-based drugs","volume":"22","author":"Kalgutkar","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1021\/acsmedchemlett.9b00687","article-title":"Recent Advances and Outlook for the Isosteric Replacement of Anilines","volume":"11","author":"Sodano","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1021\/tx200168d","article-title":"Structural Alert\/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States","volume":"24","author":"Stepan","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1001\/jamainternmed.2016.6008","article-title":"Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results","volume":"176","author":"Hwang","year":"2016","journal-title":"JAMA Intern. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.conctc.2018.08.001","article-title":"Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review","volume":"11","author":"Fogel","year":"2018","journal-title":"Contemp. Clin. Trials Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.antiviral.2014.12.015","article-title":"The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds","volume":"115","author":"John","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"V\u2019kovski, P., Kratzel, A., Steiner, S., Stalder, H., and Thiel, V. (2020). Coronavirus biology and replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol.","DOI":"10.1038\/s41579-020-00468-6"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5735","DOI":"10.1021\/acs.jcim.0c00821","article-title":"Systemic In Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server","volume":"60","author":"Xu","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.apsb.2020.08.014","article-title":"Crystal structure of SARS-CoV-2 papain-like protease","volume":"11","author":"Gao","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Bosken, Y.K., Cholko, T., Lou, Y.-C., Wu, K.-P., and Chang, C.E.A. (2020). Insights Into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.00174"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41586-020-2601-5","article-title":"Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity","volume":"587","author":"Shin","year":"2020","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Matveeva, T., Khafizova, G., and Sokornova, S. (2020). In Search of Herbal Anti-SARS-Cov2 Compounds. Front. Plant. Sci., 11.","DOI":"10.3389\/fpls.2020.589998"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e106275","DOI":"10.15252\/embj.2020106275","article-title":"Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2","volume":"39","author":"Klemm","year":"2020","journal-title":"EMBO J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1002\/jmv.25719","article-title":"COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis","volume":"92","author":"Angeletti","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s10930-020-09933-w","article-title":"An Overview of the Crystallized Structures of the SARS-CoV-2","volume":"39","author":"Ionescu","year":"2020","journal-title":"Protein J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15189","DOI":"10.1128\/JVI.79.24.15189-15198.2005","article-title":"The Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus Has Deubiquitinating Activity","volume":"79","author":"Barretto","year":"2005","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1021\/acsptsci.0c00093","article-title":"Can Papain-like Protease Inhibitors Halt SARS-CoV-2 Replication?","volume":"3","author":"Maiti","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1021\/cb500917m","article-title":"Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV","volume":"10","author":"Lee","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_63","unstructured":"OpenEye Scientific Software (2020). ROCS Version 3.4.1.0, OpenEye Scientific Software."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1021\/jm0603365","article-title":"Comparison of shape-matching and docking as virtual screening tools","volume":"50","author":"Hawkins","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_65","unstructured":"Cresset\u00ae (2020). Forge, Version 10.6, Cresset Group."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"190","DOI":"10.2174\/157340911796504314","article-title":"High content pharmacophores from molecular fields: A biologically relevant method for comparing and understanding ligands","volume":"7","author":"Cheeseright","year":"2011","journal-title":"Curr. Comput. Aided Drug Des."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"113834","DOI":"10.1016\/j.bcp.2020.113834","article-title":"In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3","volume":"174","author":"Callejo","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"107662","DOI":"10.1016\/j.jmgm.2020.107662","article-title":"Proposed model of the Dictyostelium cAMP receptors bound to cAMP","volume":"100","author":"Greenhalgh","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"ref_69","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_70","doi-asserted-by":"crossref","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: Fully automated protein\u2014Ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_71","unstructured":"Schr\u00f6dinger, L.L.C. (2020). Schr\u00f6dinger, Release 2020-4: Maestro, Schr\u00f6dinger, L.L.C."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jcc.20634","article-title":"A semiempirical free energy force field with charge-based desolvation","volume":"28","author":"Huey","year":"2007","journal-title":"J. Comput. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/prot.10613","article-title":"A hierarchical approach to all-atom protein loop prediction","volume":"55","author":"Jacobson","year":"2004","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","article-title":"On the role of the crystal environment in determining protein side-chain conformations","volume":"320","author":"Jacobson","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_76","unstructured":"Schr\u00f6dinger, L.L.C. (2020). Prime 3.0, Schr\u00f6dinger, L.L.C."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1021\/acschembio.7b00903","article-title":"Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017\u2014Utility and Limitations","volume":"13","author":"Baell","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/cmdc.200700139","article-title":"Lessons learnt from assembling screening libraries for drug discovery for neglected diseases","volume":"3","author":"Brenk","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"D930","DOI":"10.1093\/nar\/gky1075","article-title":"ChEMBL: Towards direct deposition of bioassay data","volume":"47","author":"Mendez","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An open-source program for chemistry aware data visualization and analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41557-020-0496-2","article-title":"Crowdsourcing drug discovery for pandemics","volume":"12","author":"Chodera","year":"2020","journal-title":"Nat. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.jpha.2020.08.012","article-title":"Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches","volume":"10","author":"Alamri","year":"2020","journal-title":"J. Pharm. Anal."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Gorgulla, C., PadmanabhaDas, K., Leigh, K.E., Cespugli, M., Fischer, P.D., Wang, Z.-F., Tesseyre, G., Pandita, S., Shnapir, A., and Calderaio, A. (2021). A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening. iScience, 24.","DOI":"10.1016\/j.isci.2020.102021"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Quimque, M.T., Notarte, K.I., Fernandez, R.A., Mendoza, M.A., Liman, R.A., Lim, J.A., Pilapil, L.A., Ong, J.K., Pastrana, A.M., and Khan, A. (2020). Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms. J. Biomol. Struct. Dyn., 1\u201318.","DOI":"10.26434\/chemrxiv.12170424"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Siddiqui, S., Upadhyay, S., Ahmad, R., Gupta, A., Srivastava, A., Trivedi, A., Husain, I., Ahmad, B., Ahamed, M., and Khan, M.A. (2020). Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment. J. Biomol. Struct. Dyn., 1\u201321.","DOI":"10.1080\/07391102.2020.1852117"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"933","DOI":"10.13005\/bpj\/1962","article-title":"Virtual screening of natural metabolites and antiviral drugs with potential inhibitory activity against 3CL-PRO and PL-PRO","volume":"13","year":"2020","journal-title":"Biomed. Pharmacol. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1177\/0192623312464311","article-title":"On-target and off-target-based toxicologic effects","volume":"41","author":"Rudmann","year":"2013","journal-title":"Toxicol. Pathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"17603","DOI":"10.1038\/s41598-019-54180-4","article-title":"A framework for identification of on- and off-target transcriptional responses to drug treatment","volume":"9","author":"Huang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00894-019-4032-5","article-title":"Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3\u03b2 inhibitors","volume":"25","author":"Osman","year":"2019","journal-title":"J. Mol. Model."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1021\/acs.jmedchem.6b01437","article-title":"Recent Advances in Scaffold Hopping","volume":"60","author":"Hu","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"16469","DOI":"10.1038\/s41598-018-34677-0","article-title":"Scaffold-Hopping from Synthetic Drugs by Holistic Molecular Representation","volume":"8","author":"Grisoni","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1111\/bph.15152","article-title":"Ethaninidothioic acid (R5421) is not a selective inhibitor of platelet phospholipid scramblase activity","volume":"177","author":"Bonna","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational methods in drug discovery","volume":"66","author":"Sliwoski","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"12964","DOI":"10.1039\/C6CP01555G","article-title":"Comprehensive evaluation of ten docking programs on a diverse set of protein-ligand complexes: The prediction accuracy of sampling power and scoring power","volume":"18","author":"Wang","year":"2016","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Vieira, T.F., and Sousa, S.F. (2019). Comparing AutoDock and Vina in Ligand\/Decoy Discrimination for Virtual Screening. Appl. Sci., 9.","DOI":"10.3390\/app9214538"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1021\/acs.jcim.9b00778","article-title":"Autodock Vina Adopts More Accurate Binding Poses but Autodock4 Forms Better Binding Affinity","volume":"60","author":"Nguyen","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1021\/acs.jcim.8b00312","article-title":"Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark","volume":"58","author":"Gaillard","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Boittier, E.D., Tang, Y.Y., Buckley, M.E., Schuurs, Z.P., Richard, D.J., and Gandhi, N.S. (2020). Assessing Molecular Docking Tools to Guide Targeted Drug Discovery of CD38 Inhibitors. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155183"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s13321-019-0373-4","article-title":"DLIGAND2: An improved knowledge-based energy function for protein-ligand interactions using the distance-scaled, finite, ideal-gas reference state","volume":"11","author":"Chen","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"104697","DOI":"10.1016\/j.antiviral.2019.104697","article-title":"In silico and in vitro analysis of small molecules and natural compounds targeting the 3CL protease of feline infectious peritonitis virus","volume":"174","author":"Theerawatanasirikul","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Jeong, J., Kim, H., and Choi, J. (2019). In Silico Molecular Docking and In Vivo Validation with Caenorhabditis elegans to Discover Molecular Initiating Events in Adverse Outcome Pathway Framework: Case Study on Endocrine-Disrupting Chemicals with Estrogen and Androgen Receptors. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051209"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-70042-w","article-title":"Structure\/activity virtual screening and in vitro testing of small molecule inhibitors of 8-hydroxy-5-deazaflavin: NADPH oxidoreductase from gut methanogenic bacteria","volume":"10","author":"Cuccioloni","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1021\/ci300030u","article-title":"Performance Evaluation of 2D Fingerprint and 3D Shape Similarity Methods in Virtual Screening","volume":"52","author":"Hu","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s10822-020-00318-w","article-title":"Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer\u2019s disease","volume":"34","author":"Tripathi","year":"2020","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jmgm.2013.09.005","article-title":"Could MM-GBSA be accurate enough for calculation of absolute protein\/ligand binding free energies?","volume":"46","author":"Mulakala","year":"2013","journal-title":"J. Mol. Graph. Model."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the Performance of the MM\/PBSA and MM\/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations","volume":"51","author":"Hou","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-Point Binding Free Energy Calculation with MM\/PBSA and MM\/GBSA: Strategies and Applications in Drug Design","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.bmcl.2019.02.017","article-title":"Discovery of NR2B-selective antagonists via scaffold hopping and pharmacokinetic profile optimization","volume":"29","author":"Anan","year":"2019","journal-title":"Bioorgan. Med. Chem. Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","article-title":"Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus","volume":"182","author":"Korber","year":"2020","journal-title":"Cell"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41586-020-2798-3","article-title":"SARS-CoV-2 vaccines in development","volume":"586","author":"Krammer","year":"2020","journal-title":"Nature"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1126\/science.abf0357","article-title":"Ensuring vaccine safety","volume":"370","author":"Knipe","year":"2020","journal-title":"Science"},{"key":"ref_114","unstructured":"Chemical Computing Group ULC (2020). Molecular Operating Environment (MOE), 2019.01, Chemical Computing Group."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/jcc.540150503","article-title":"ICM\u2014A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation","volume":"15","author":"Abagyan","year":"1994","journal-title":"J. Comput. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1002\/jcc.21797","article-title":"Fast docking using the CHARMM force field with EADock DSS","volume":"32","author":"Grosdidier","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Dallakyan, S., and Olson, A.J. (2015). Small-Molecule Library Screening by Docking with PyRx. Chemical Biology, Springer.","DOI":"10.1007\/978-1-4939-2269-7_19"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13321-019-0362-7","article-title":"DockRMSD: An open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism","volume":"11","author":"Bell","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_121","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_122","unstructured":"Molexus IVS (2020). Molegro Molecular Viewer (MMV), Version 7.0., Molexus."},{"key":"ref_123","unstructured":"ChemAxon (2020). MarvinSketch, Version 20.16, ChemAxon Ltd."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/ci200387c","article-title":"Revisiting the general solubility equation: In silico prediction of aqueous solubility incorporating the effect of topographical polar surface area","volume":"52","author":"Ali","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1021\/ci500467k","article-title":"iLOGP: A simple, robust, and efficient description of n-octanol\/water partition coefficient for drug design using the GB\/SA approach","volume":"54","author":"Daina","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1248\/cpb.40.127","article-title":"Simple Method of Calculating Octanol\/Water Partition Coefficient","volume":"40","author":"Moriguchi","year":"1992","journal-title":"Chem. Pharm. Bull."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1134\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:27:08Z","timestamp":1760160428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,20]]},"references-count":126,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26041134"],"URL":"https:\/\/doi.org\/10.3390\/molecules26041134","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,20]]}}}