{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:34:14Z","timestamp":1787045654876,"version":"build-2736575974"},"reference-count":28,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["170631"],"award-info":[{"award-number":["170631"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["172639"],"award-info":[{"award-number":["172639"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["36194"],"award-info":[{"award-number":["36194"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["41067"],"award-info":[{"award-number":["41067"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI134229"],"award-info":[{"award-number":["R01AI134229"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011094","name":"Public Health Agency of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011094","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The rapid global spread of the SARS-CoV-2 virus facilitated the development of novel direct-acting antiviral agents (DAAs). The papain-like protease (PLpro) has been proposed as one of the major SARS-CoV-2 targets for DAAs due to its dual role in processing viral proteins and facilitating the host\u2019s immune suppression. This dual role makes identifying small molecules that can effectively neutralize SARS-CoV-2 PLpro activity a high-priority task. However, PLpro drug discovery faces a significant challenge due to the high mobility and induced-fit effects in the protease\u2019s active site. Herein, we virtually screened the ZINC20 database with Deep Docking (DD) to identify prospective noncovalent PLpro binders and combined ultra-large consensus docking with two pharmacophore (ph4)-filtering strategies. The analysis of active compounds revealed their somewhat-limited diversity, likely attributed to the induced-fit nature of PLpro\u2019s active site in the crystal structures, and therefore, the use of rigid docking protocols poses inherited limitations. The top hits were assessed against recombinant viral proteins and live viruses, demonstrating desirable inhibitory activities. The best compound VPC-300195 (IC50: 15 \u03bcM) ranks among the top noncovalent PLpro inhibitors discovered through in silico methodologies. In the search for novel SARS-CoV-2 PLpro-specific chemotypes, the identified inhibitors could serve as diverse templates for the development of effective noncovalent PLpro inhibitors.<\/jats:p>","DOI":"10.1021\/acs.jcim.2c01641","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T15:06:55Z","timestamp":1679065615000},"page":"2158-2169","source":"Crossref","is-referenced-by-count":21,"title":["Large-Scale Virtual\nScreening for the Discovery of\nSARS-CoV\u20112 Papain-like Protease (PLpro) Non-covalent Inhibitors"],"prefix":"10.1021","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-6276","authenticated-orcid":true,"given":"Olivia","family":"Garland","sequence":"first","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh-Tien","family":"Ton","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoeib","family":"Moradi","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Smith","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]},{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Kovacic","sequence":"additional","affiliation":[{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurtis","family":"Ng","sequence":"additional","affiliation":[{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Pandey","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuqiang","family":"Ban","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeyong","family":"Lee","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Vuckovic","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam J.","family":"Worrall","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8235-6080","authenticated-orcid":true,"given":"Robert N.","family":"Young","sequence":"additional","affiliation":[{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0490-4747","authenticated-orcid":true,"given":"Ralph","family":"Pantophlet","sequence":"additional","affiliation":[{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]},{"name":"Simon Fraser University , , , ,","place":["Burnaby, British Columbia, Canada, V5A 1S6"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4058-9425","authenticated-orcid":true,"given":"Natalie C. J.","family":"Strynadka","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-1439","authenticated-orcid":true,"given":"Artem","family":"Cherkasov","sequence":"additional","affiliation":[{"name":"University of British Columbia , , , ,","place":["Vancouver, British Columbia, Canada, V6H 3Z6"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"2026081804434582300_cit1","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1056\/NEJMOA2108891\/SUPPL_FILE\/NEJMOA2108891_DISCLOSURES.PDF","article-title":"Effectiveness\nof Covid-19 Vaccines against the B.1.617.2 (Delta) Variant","volume":"385","author":"Lopez\nBernal","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"2026081804434582300_cit2","doi-asserted-by":"publisher","first-page":"8686","DOI":"10.1021\/ACS.JMEDCHEM.2C00404","article-title":"Evolutionary and\nStructural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir","volume":"65","author":"Yang","year":"2022","journal-title":"J. Med. Chem."},{"key":"2026081804434582300_cit3","doi-asserted-by":"crossref","DOI":"10.1101\/2022.07.02.495455","article-title":"SARS-CoV-2\n3CLpro Mutations Confer Resistance to Paxlovid (Nirmatrelvir\/Ritonavir)\nin a VSV-Based, Non-Gain-of-Function System","author":"Heilmann","year":"2022"},{"key":"2026081804434582300_cit4","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41586-020-2601-5","article-title":"Papain-like Protease\nRegulates SARS-CoV-2 Viral Spread and Innate Immunity","volume":"587","author":"Shin","year":"2020","journal-title":"Nature"},{"key":"2026081804434582300_cit5","doi-asserted-by":"publisher","first-page":"6689","DOI":"10.1128\/JVI.02220-08","article-title":"Severe\nAcute Respiratory Syndrome Coronavirus Papain-like Protease Ubiquitin-like\nDomain and Catalytic Domain Regulate Antagonism of IRF3 and NF-KappaB\nSignaling","volume":"83","author":"Frieman","year":"2009","journal-title":"J. Virol."},{"key":"2026081804434582300_cit6","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/J.APSB.2020.08.014","article-title":"Crystal Structure of SARS-CoV-2 Papain-like\nProtease","volume":"11","author":"Gao","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"2026081804434582300_cit7","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd4596","article-title":"Activity Profiling and Crystal Structures\nof Inhibitor-Bound\nSARS-CoV-2 Papain-like Protease: A Framework for Anti\u2013COVID-19\nDrug Design","volume":"6","author":"Rut","year":"2020","journal-title":"Sci. Adv."},{"key":"2026081804434582300_cit8","doi-asserted-by":"publisher","first-page":"16119","DOI":"10.1073\/PNAS.0805240105\/SUPPL_FILE\/0805240105SI.PDF","article-title":"A Noncovalent\nClass of Papain-like Protease\/Deubiquitinase Inhibitors Blocks SARS\nVirus Replication","volume":"105","author":"Ratia","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026081804434582300_cit9","doi-asserted-by":"publisher","first-page":"2940","DOI":"10.1021\/ACS.JMEDCHEM.1C01307\/SUPPL_FILE\/JM1C01307_SI_002.XLSX","article-title":"Design of\nSARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging\nBinding Cooperativity","volume":"65","author":"Shen","year":"2022","journal-title":"J. Med. Chem."},{"key":"2026081804434582300_cit10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-21060-3","article-title":"Structure\nof Papain-like Protease from SARS-CoV-2 and\nIts Complexes with Non-Covalent Inhibitors","volume":"12","author":"Osipiuk","year":"2021","journal-title":"Nat. Commun."},{"key":"2026081804434582300_cit11","doi-asserted-by":"publisher","first-page":"27381","DOI":"10.1073\/PNAS.2010470117\/SUPPL_FILE\/PNAS.2010470117.SD01.TXT","article-title":"Identify Potent SARS-CoV-2 Main Protease Inhibitors\nvia Accelerated Free Energy Perturbation-Based Virtual Screening of\nExisting Drugs","volume":"117","author":"Li","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026081804434582300_cit12","doi-asserted-by":"publisher","first-page":"15960","DOI":"10.1039\/D1SC05579H","article-title":"Automated\nDiscovery of Noncovalent Inhibitors of SARS-CoV-2\nMain Protease by Consensus Deep Docking of 40 Billion Small Molecules","volume":"12","author":"Gentile","year":"2021","journal-title":"Chem. Sci."},{"key":"2026081804434582300_cit13","doi-asserted-by":"crossref","DOI":"10.1021\/acs.jcim.2c00693","article-title":"Structure-Based\nIdentification of Naphthoquinones and Derivatives\nas Novel Inhibitors of Main Protease Mpro and Papain-like Protease\nPLpro of SARS-CoV-2","author":"Santos","year":"2022"},{"key":"2026081804434582300_cit14","doi-asserted-by":"publisher","DOI":"10.15252\/EMBJ.2020106275","article-title":"Mechanism and Inhibition\nof the Papain-like\nProtease, PLpro, of SARS-CoV-2","volume":"39","author":"Klemm","year":"2020","journal-title":"EMBO J."},{"key":"2026081804434582300_cit15","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1021\/ACSCENTSCI.1C00519\/ASSET\/IMAGES\/LARGE\/OC1C00519_0008","article-title":"Discovery\nof SARS-CoV-2 Papain-like Protease Inhibitors through a Combination\nof High-Throughput Screening and a FlipGFP-Based Reporter Assay","volume":"7","author":"Ma","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"2026081804434582300_cit16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-020-20718-8","article-title":"The Complex Structure\nof GRL0617 and SARS-CoV-2 PLpro Reveals a Hot\nSpot for Antiviral Drug Discovery","volume":"12","author":"Fu","year":"2021","journal-title":"Nat. Commun."},{"key":"2026081804434582300_cit17","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1186\/s40064-016-1972-4","article-title":"CrossDocker:\nA Tool for Performing Cross-Docking Using Autodock Vina","volume":"5","author":"Shamsara","year":"2016","journal-title":"Springerplus"},{"key":"2026081804434582300_cit18","doi-asserted-by":"crossref","DOI":"10.1101\/2021.02.13.431008","article-title":"Potent,\nNovel SARS-CoV-2 PLpro Inhibitors\nBlock Viral Replication in Monkey and Human Cell Cultures","author":"Shen","year":"2021"},{"key":"2026081804434582300_cit19","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1021\/ACSCENTSCI.0C00229\/ASSET\/IMAGES\/MEDIUM\/OC0C00229_M005","article-title":"Deep Docking:\nA Deep Learning Platform for Augmentation of Structure Based Drug\nDiscovery","volume":"6","author":"Gentile","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"2026081804434582300_cit20","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/s41596-021-00659-2","article-title":"Artificial\nIntelligence\u2013Enabled Virtual Screening of Ultra-Large Chemical\nLibraries with Deep Docking","volume":"17","author":"Gentile","year":"2022","journal-title":"Nat. Protoc."},{"key":"2026081804434582300_cit21","doi-asserted-by":"publisher","first-page":"2887","DOI":"10.1021\/JM9602928","article-title":"The Properties of\nKnown Drugs. 1. Molecular Frameworks","volume":"39","author":"Bemis","year":"1996","journal-title":"J. Med.\nChem."},{"key":"2026081804434582300_cit22","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/SCIENCE.ABL4784\/SUPPL_FILE\/SCIENCE.ABL4784_MDAR_REPRODUCIBILITY_CHECKLIST.PDF","article-title":"An Oral SARS-CoV-2 Mpro Inhibitor\nClinical Candidate for the Treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"2026081804434582300_cit23","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1128\/JVI.01819-20\/ASSET\/B1373F7D-5082-4E2D-B57C-251A1F0C3C9D\/ASSETS\/IMAGES\/LARGE\/JVI.01819-20-F007","article-title":"A Comparative Analysis of SARS-CoV-2\nAntivirals Characterizes 3CL pro Inhibitor PF-00835231 as a Potential\nNew Treatment for COVID-19","volume":"95","author":"de\nVries","year":"2021","journal-title":"J. Virol."},{"key":"2026081804434582300_cit24","doi-asserted-by":"publisher","first-page":"12725","DOI":"10.1021\/ACS.JMEDCHEM.0C01063\/SUPPL_FILE\/JM0C01063_SI_002.PDF","article-title":"Discovery\nof Ketone-Based\nCovalent Inhibitors of Coronavirus 3CL Proteases for the Potential\nTherapeutic Treatment of COVID-19","volume":"63","author":"Hoffman","year":"2020","journal-title":"J. Med. Chem."},{"key":"2026081804434582300_cit25","doi-asserted-by":"publisher","first-page":"4914","DOI":"10.1002\/JPS.21756","article-title":"N-(3,4-Dimethoxyphenethyl)-4-(6,7-Dimethoxy-3,4-Dihydroisoquinolin-2\u00ad[1H]-Yl)-6,7-Dimethoxyquinazolin-2-Amine\n(CP-100,356) as a \u201cChemical Knock-out Equivalent\u201d to\nAssess the Impact of Efflux Transporters on Oral Drug Absorption in\nthe Rat","volume":"98","author":"Kalgutkar","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"2026081804434582300_cit26","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/J.CELL.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on\nACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"2026081804434582300_cit27","doi-asserted-by":"publisher","first-page":"105252","DOI":"10.1016\/J.ANTIVIRAL.2022.105252","article-title":"Remdesivir,\nMolnupiravir and Nirmatrelvir remain active\nagainst SARS-CoV-2 Omicron and other variants of concern","volume":"198","author":"Vangeel","year":"2022","journal-title":"Antiviral Res."},{"key":"2026081804434582300_cit28","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PBIO.3001091","article-title":"A Plasmid\nDNA-Launched SARS-CoV-2 Reverse Genetics System and Coronavirus Toolkit\nfor COVID-19 Research","volume":"19","author":"Rihn","year":"2021","journal-title":"PLoS Biol."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.2c01641","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/63\/7\/2158\/8909320\/ci2c01641.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/63\/7\/2158\/8909320\/ci2c01641.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:19:22Z","timestamp":1787044762000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/63\/7\/2158\/850332\/Large-Scale-Virtual-Screening-for-the-Discovery-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,3,17]]},"published-print":{"date-parts":[[2023,4,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.2c01641","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,17]]}}}