{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:38:23Z","timestamp":1792607903361,"version":"4.5.0"},"reference-count":101,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Food and Drug Administration (FDA)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures of PLpro complexed ligands have been deposited in the Protein Data Bank, offering valuable insight into ligand-binding features that could aid the discovery and development of effective COVID-19 treatments targeting PLpro. In this study, we reviewed and analyzed these 3D structures, focusing on the key residues involved in ligand interactions. Our analysis revealed that most inhibitors bind to PLpro\u2019s substrate recognition sites S3\/S4 and SUb2. While these sites are highly attractive and have been extensively explored, other potential binding regions, such as SUb1 and the Zn(II) domain, are less explored and may hold untapped potential for future COVID-19 drug discovery and development. Our structural analysis provides insights into the molecular features of PLpro that could accelerate the development of novel therapeutics targeting this essential viral enzyme.<\/jats:p>","DOI":"10.3390\/molecules30030491","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T05:49:54Z","timestamp":1737611394000},"page":"491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme"],"prefix":"10.3390","volume":"30","author":[{"given":"Ann","family":"Varghese","sequence":"first","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailang","family":"Liu","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Guo","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Dong","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tucker A.","family":"Patterson","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-3968","authenticated-orcid":false,"given":"Huixiao","family":"Hong","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1080\/19397038.2021.1964634","article-title":"A perspective of COVID 19 impact on global economy, energy and environment","volume":"14","author":"Priya","year":"2021","journal-title":"Int. J. Sustain. Eng."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41562-021-01096-7","article-title":"Socioeconomic impacts of COVID-19 in low-income countries","volume":"5","author":"Josephson","year":"2021","journal-title":"Nat. Hum. Behav."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jare.2020.03.005","article-title":"COVID-19 infection: Emergence, transmission, and characteristics of human coronaviruses","volume":"24","author":"Shereen","year":"2020","journal-title":"J. Adv. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2313","DOI":"10.1002\/rmv.2313","article-title":"COVID-19 vaccines and variants of concern: A review","volume":"32","year":"2022","journal-title":"Rev. Med. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Domingo, P., and De Benito, N. (2021). Alpha variant SARS-CoV-2 infection: How it all starts. eBioMedicine, 74.","DOI":"10.1016\/j.ebiom.2021.103703"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E1059","DOI":"10.1503\/cmaj.1095949","article-title":"Alpha, Beta, Delta, Gamma: What\u2019s important to know about SARS-CoV-2 variants of concern?","volume":"193","author":"Duong","year":"2021","journal-title":"Can. Med. Assoc. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1126\/science.372.6549.1375","article-title":"Delta variant triggers new phase in the pandemic","volume":"372","author":"Kupferschmidt","year":"2021","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2068883","DOI":"10.1080\/21645515.2022.2068883","article-title":"Delta variant (B.1.617.2) of SARS-CoV-2: Mutations, impact, challenges and possible solutions","volume":"18","author":"Dhawan","year":"2022","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1002\/jmv.27588","article-title":"Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines","volume":"94","author":"Araf","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1140\/epjp\/s13360-021-02321-y","article-title":"Omicron: A mysterious variant of concern","volume":"137","author":"Gowrisankar","year":"2022","journal-title":"Eur. Phys. J. Plus"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"m3862","DOI":"10.1136\/bmj.m3862","article-title":"Virology, transmission, and pathogenesis of SARS-CoV-2","volume":"371","author":"Cevik","year":"2020","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s15010-020-01486-5","article-title":"Differences and similarities between SARS-CoV and SARS-CoV-2: Spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases","volume":"48","author":"Rossi","year":"2020","journal-title":"Infection"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.5501\/wjv.v11.i1.40","article-title":"Animal models for SARS-CoV-2 and SARS-CoV-1 pathogenesis, transmission and therapeutic evaluation","volume":"11","author":"Saravanan","year":"2022","journal-title":"World J. Virol."},{"key":"ref_14","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_15","first-page":"30","article-title":"An Introduction to SARS Coronavirus 2; Comparative Analysis with MERS and SARS Coronaviruses: A Brief Review","volume":"49","author":"Taherizadeh","year":"2020","journal-title":"Iran. J. Public. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The trinity of COVID-19: Immunity, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112559","DOI":"10.1016\/j.ejmech.2020.112559","article-title":"Fight against novel coronavirus: A perspective of medicinal chemists","volume":"201","author":"Amin","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"The Lancet"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.molcel.2020.04.022","article-title":"A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells","volume":"78","author":"Hoffmann","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","article-title":"Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV","volume":"11","author":"Ou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","article-title":"Structural basis of receptor recognition by SARS-CoV-2","volume":"581","author":"Shang","year":"2020","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00408-020-00408-4","article-title":"ACE2: The Major Cell Entry Receptor for SARS-CoV-2","volume":"198","author":"Scialo","year":"2020","journal-title":"Lung"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sakkiah, S., Guo, W., Pan, B., Ji, Z., Yavas, G., Azevedo, M., Hawes, J., Patterson, T.A., and Hong, H. (2021). Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations. Front. Chem., 8.","DOI":"10.3389\/fchem.2020.622632"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, M., Major, M., and Hong, H. (2023). Distinct Conformations of SARS-CoV-2 Omicron Spike Protein and Its Interaction with ACE2 and Antibody. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043774"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mukherjee, R., and Dikic, I. (2023). Proteases of SARS Coronaviruses. Encyclopedia of Cell Biology, Elsevier. Available online: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/B9780128216187001115.","DOI":"10.1016\/B978-0-12-821618-7.00111-5"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Naqvi, A.A., Fatima, K., Mohammad, T., Fatima, U., Singh, I.K., Singh, A., Atif, S.M., Hariprasad, G., Hasan, G.M., and Hassan, M.I. (2020). Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim. Biophys. Acta BBA\u2014Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2020.165878"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103727","DOI":"10.1016\/j.drudis.2023.103727","article-title":"Analyzing 3D structures of the SARS-CoV-2 main protease reveals structural features of ligand binding for COVID-19 drug discovery","volume":"28","author":"Xu","year":"2023","journal-title":"Drug Discov. Today"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e151","DOI":"10.1002\/mco2.151","article-title":"The SARS-CoV-2 main protease (M pro): Structure, function, and emerging therapies for COVID-19","volume":"3","author":"Hu","year":"2022","journal-title":"MedComm"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ullrich, S., and Nitsche, C. (2020). The SARS-CoV-2 main protease as drug target. Bioorg Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127377"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"442","DOI":"10.2174\/1568026620666201207095117","article-title":"An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors","volume":"21","author":"Sabbah","year":"2021","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_34","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":"Mesecar","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1073\/pnas.0510851103","article-title":"Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme","volume":"103","author":"Ratia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.antiviral.2017.11.001","article-title":"Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein","volume":"149","author":"Lei","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.3390\/v2081803","article-title":"Coronavirus Genomics and Bioinformatics Analysis","volume":"2","author":"Woo","year":"2010","journal-title":"Viruses"},{"key":"ref_38","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_39","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_40","doi-asserted-by":"crossref","unstructured":"Ratia, K., Kilianski, A., Baez-Santos, Y.M., Baker, S.C., and Mesecar, A. (2014). Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004113"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41579-018-0020-5","article-title":"ISG15 in antiviral immunity and beyond","volume":"16","author":"Perng","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The Ubiquitin Code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33220","DOI":"10.1074\/jbc.M104097200","article-title":"The Autocatalytic Release of a Putative RNA Virus Transcription Factor from Its Polyprotein Precursor Involves Two Paralogous Papain-like Proteases That Cleave the Same Peptide Bond","volume":"276","author":"Ziebuhr","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"104661","DOI":"10.1016\/j.antiviral.2019.104661","article-title":"Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease","volume":"174","author":"Clasman","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/prot.20802","article-title":"Binding site-based classification of coronaviral papain-like proteases","volume":"62","author":"Sulea","year":"2006","journal-title":"Proteins Struct. Funct. Bioinforma"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Snyder, N.A., and Silva, G.M. (2021). Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.101077"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2147\/HIV.S79956","article-title":"HIV protease inhibitors: A review of molecular selectivity and toxicity","volume":"7","author":"Wang","year":"2015","journal-title":"HIVAIDS\u2014Res. Palliat. Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1021\/jm201278q","article-title":"Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants","volume":"55","author":"Kazmierski","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of COVID-19\u2014Final Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1056\/NEJMoa2116846","article-title":"Early Remdesivir to Prevent Progression to Severe COVID-19 in Outpatients","volume":"386","author":"Gottlieb","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sakander, N., Ahmed, A., Bhardwaj, M., Kumari, D., Nandi, U., and Mukherjee, D. (2024). A path from synthesis to emergency use authorization of molnupiravir as a COVID-19 therapy. Bioorganic Chem., 147.","DOI":"10.1016\/j.bioorg.2024.107379"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1016\/j.drudis.2019.06.014","article-title":"Drug repurposing: A promising tool to accelerate the drug discovery process","volume":"24","author":"Parvathaneni","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e202100455","DOI":"10.1002\/cmdc.202100455","article-title":"Drug Repurposing for the SARS-CoV-2 Papain-Like Protease","volume":"17","author":"Cho","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kulandaisamy, R., Kushwaha, T., Dalal, A., Kumar, V., Singh, D., Baswal, K., Sharma, P., Praneeth, K., Jorwal, P., and Kayampeta, S.R. (2022). Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.877813"},{"key":"ref_56","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_57","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_58","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_59","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbrc.2020.11.083","article-title":"Molecular docking of potential SARS-CoV-2 papain-like protease inhibitors","volume":"538","author":"Li","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gao, H., Dai, R., and Su, R. (2023). Computer-aided drug design for the pain-like protease (PLpro) inhibitors against SARS-CoV-2. Biomed Pharmacother., 159.","DOI":"10.1016\/j.biopha.2023.114247"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tian, X., Zhao, Q., Chen, X., Peng, Z., Tan, X., Wang, Q., Chen, L., and Yang, Y. (2022). Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.817715"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"16899","DOI":"10.18632\/oncotarget.24458","article-title":"Competitive docking model for prediction of the human nicotinic acetylcholine receptor \u03b17 binding of tobacco constituents","volume":"9","author":"Ng","year":"2018","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/10629360290002235","article-title":"An integrated \u201c4-phase\u201d approach for setting endocrine disruption screening priorities--phase I and II predictions of estrogen receptor binding affinity","volume":"13","author":"Shi","year":"2002","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_64","first-page":"1","article-title":"Molecular docking-based virtual screening and computational investigations of biomolecules (curcumin analogs) as potential lead inhibitors for SARS-CoV-2 papain-like protease","volume":"71","author":"Fakih","year":"2024","journal-title":"Pharmacia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"139353","DOI":"10.1016\/j.molstruc.2024.139353","article-title":"Modification of ionic liquid and lactoferrin-based small molecules as potential therapeutics against SARS-CoV-2: Molecular docking disclosed the predictable results","volume":"1319","author":"Senan","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/10590501.2018.1537148","article-title":"Target-specific toxicity knowledgebase (TsTKb): A novel toolkit for in silico predictive toxicology","volume":"36","author":"Li","year":"2018","journal-title":"J. Environ. Sci. Health Part. C"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1177\/095632029800900602","article-title":"Identification of HIV-1 Integrase Inhibitors Based on a Four-Point Pharmacophore","volume":"9","author":"Hong","year":"1998","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Vald\u00e9s-Albuernes, J.L., D\u00edaz-Pico, E., Alfaro, S., and Caballero, J. (2024). Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1374364"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1080\/07391102.2022.2071340","article-title":"Promising antivirals for PLpro of SARS-CoV-2 using virtual screening, molecular docking, dynamics, and MMPBSA","volume":"41","author":"Kumari","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"104334","DOI":"10.1016\/j.arabjc.2022.104334","article-title":"Pharmacophore model-aided virtual screening combined with comparative molecular docking and molecular dynamics for identification of marine natural products as SARS-CoV-2 papain-like protease inhibitors","volume":"15","author":"Thangavel","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1136\/mp.53.1.8","article-title":"x Ray crystallography","volume":"53","author":"Smyth","year":"2000","journal-title":"Mol. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1074\/mcp.O113.030239","article-title":"An Introduction to Biological NMR Spectroscopy","volume":"12","author":"Marion","year":"2013","journal-title":"Mol. Cell Proteom."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/cbdd.13388","article-title":"Homology modeling in drug discovery: Overview, current applications, and future perspectives","volume":"93","author":"Muhammed","year":"2019","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41467-021-21060-3","article-title":"Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors","volume":"12","author":"Osipiuk","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.str.2006.06.012","article-title":"Structural Basis of Ubiquitin Recognition by the Deubiquitinating Protease USP2","volume":"14","author":"Renatus","year":"2006","journal-title":"Structure"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/pro.3289","article-title":"PDBsum: Structural summaries of PDB entries","volume":"27","author":"Laskowski","year":"2018","journal-title":"Protein Sci."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Bosken, Y.K., Cholko, T., Lou, Y.C., Wu, K.P., and Chang Cen, 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_78","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_79","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\u2013COVID-19 drug design","volume":"6","author":"Rut","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1038\/s41467-023-38031-5","article-title":"Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin","volume":"14","author":"Wydorski","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1107\/S1399004713031040","article-title":"Structural basis for catalysis and ubiquitin recognition by the Severe acute respiratory syndrome coronavirus papain-like protease","volume":"70","author":"Chou","year":"2014","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1039\/D3SC00166K","article-title":"Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches","volume":"14","author":"Shao","year":"2023","journal-title":"Chem. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Srinivasan, V., Brognaro, H., Prabhu, P.R., de Souza, E.E., G\u00fcnther, S., Reinke, P.Y., Lane, T.J., Ginn, H., Han, H., and Ewert, W. (2022). Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03737-7"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.chembiol.2021.04.020","article-title":"Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2","volume":"28","author":"Shan","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s13238-021-00836-9","article-title":"High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors","volume":"12","author":"Zhao","year":"2021","journal-title":"Protein Cell"},{"key":"ref_86","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_87","doi-asserted-by":"crossref","unstructured":"van Vliet, V.J., Huynh, N., Pal\u00e0, J., Patel, A., Singer, A., Slater, C., Chung, J., van Huizen, M., Teyra, J., and Miersch, S. (2022). Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site. PLOS Pathog., 18.","DOI":"10.1371\/journal.ppat.1011065"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Wang, Q., Chen, G., He, J., Li, J., Xiong, M., Su, H., Li, M., Hu, H., and Xu, Y. (2023). Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108633"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.adm9724","article-title":"Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model","volume":"383","author":"Tan","year":"2024","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1021\/acscentsci.1c00519","article-title":"Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay","volume":"7","author":"Ma","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Shen, Z., Ratia, K., Cooper, L., Kong, D., Lee, H., Kwon, Y., Li, Y., Alqarni, S., Huang, F., and Dubrovskyi, O. (2021). Potent, Novel SARS-CoV-2 PLpro Inhibitors Block Viral Replication in Monkey and Human Cell Cultures. BioRxiv.","DOI":"10.1101\/2021.02.13.431008"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Calleja, D.J., Kuchel, N., Lu, B.G., Birkinshaw, R.W., Klemm, T., Doerflinger, M., Cooney, J.P., Mackiewicz, L., Au, A.E., and Yap, Y.Q. (2022). Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.861209"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.chembiol.2021.11.006","article-title":"Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses","volume":"29","author":"Napolitano","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1021\/acsmedchemlett.4c00238","article-title":"Fragment-Based Screen of SARS-CoV-2 Papain-like Protease (PL pro)","volume":"15","author":"Taylor","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Ewert, W., G\u00fcnther, S., Miglioli, F., Falke, S., Reinke, P.Y., Niebling, S., G\u00fcnther, C., Han, H., Srinivasan, V., and Brognaro, H. (2022). Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.832431"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Calleja, D.J., Lessene, G., and Komander, D. (2022). Inhibitors of SARS-CoV-2 PLpro. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.876212"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6219","DOI":"10.1038\/s41467-024-50566-9","article-title":"Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape","volume":"15","author":"Wu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Perlinska, A.P., Stasiulewicz, A., Nguyen, M.L., Swiderska, K., Zmudzinski, M., Maksymiuk, A.W., Drag, M., and Sulkowska, J.I. (2022). Amino acid variants of SARS-CoV-2 papain-like protease have impact on drug binding. PLoS Comput. Biol., 18.","DOI":"10.1371\/journal.pcbi.1010667"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.molcel.2016.04.016","article-title":"Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease","volume":"62","author":"Ekkebus","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14918","DOI":"10.1074\/jbc.274.21.14918","article-title":"A Human RNA Viral Cysteine Proteinase That Depends upon a Unique Zn2+-binding Finger Connecting the Two Domains of a Papain-like Fold","volume":"274","author":"Herold","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Yang, M., Mariano, J., Su, R., Smith, C.E., Das, S., Gill, C., Andresson, T., Loncarek, J., Tsai, Y.C., and Weissman, A.M. (2023). SARS-CoV-2 papain-like protease plays multiple roles in regulating cellular proteins in the endoplasmic reticulum. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.105346"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/3\/491\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:34:10Z","timestamp":1759919650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/3\/491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":101,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["molecules30030491"],"URL":"https:\/\/doi.org\/10.3390\/molecules30030491","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]}}}