{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:10:22Z","timestamp":1790878222860,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Agency in Poland","award":["2020\/ABM\/SARS\/1"],"award-info":[{"award-number":["2020\/ABM\/SARS\/1"]}]},{"name":"National Science Center, Poland","award":["UMO-2020\/01\/0\/NZ1\/00063"],"award-info":[{"award-number":["UMO-2020\/01\/0\/NZ1\/00063"]}]},{"DOI":"10.13039\/501100001870","name":"Foundation for Polish Science","doi-asserted-by":"publisher","award":["TEAM\/2017-4\/32"],"award-info":[{"award-number":["TEAM\/2017-4\/32"]}],"id":[{"id":"10.13039\/501100001870","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wroclaw Medical University Subvention","award":["SUB.D030.21.029"],"award-info":[{"award-number":["SUB.D030.21.029"]}]},{"name":"Special Research Facility grant from Ministry of Science and Higher Education","award":["No. 96\/E-394\/SPUB\/SP\/2019"],"award-info":[{"award-number":["No. 96\/E-394\/SPUB\/SP\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>More than a year has passed since the world began to fight the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the Coronavirus disease 2019 (COVID-19) pandemic, and still it spreads around the world, mutating at the same time. One of the sources of compounds with potential antiviral activity is Traditional Chinese Medicinal (TCM) plants used in China in the supportive treatment of COVID-19. Reynoutria japonica is important part of the Shu Feng Jie Du Granule\/Capsule-TCM herbal formula, recommended by China Food and Drug Administration (CFDA) for treatment of patients with H1N1- and H5N9-induced acute lung injury and is also used in China to treat COVID-19, mainly combined with other remedies. In our study, 25 compounds from rhizomes of R. japonica and Reynoutria sachalinensis (related species), were docked into the binding site of SARS-CoV-2 main protease. Next, 11 of them (vanicoside A, vanicoside B, resveratrol, piceid, emodin, epicatechin, epicatechin gallate, epigallocatechin gallate, procyanidin B2, procyanidin C1, procyanidin B2 3,3\u2019-di-O-gallate) as well as extracts and fractions from rhizomes of R. japonica and R. sachalinensis were tested in vitro using a fluorescent peptide substrate. Among the tested phytochemicals the best results were achieved for vanicoside A and vanicoside B with moderate inhibition of SARS-CoV-2 Mpro, IC50 = 23.10 \u00b5M and 43.59 \u00b5M, respectively. The butanol fractions of plants showed the strongest inhibition of SARS-CoV-2 Mpro (IC50 = 4.031 \u00b5g\/mL for R. sachalinensis and IC50 = 7.877 \u00b5g\/mL for R. japonica). As the main constituents of butanol fractions, besides the phenylpropanoid disaccharide esters (e.g., vanicosides), are highly polymerized procyanidins, we suppose that they could be responsible for their strong inhibitory properties. As inhibition of SARS-CoV-2 main protease could prevent the replication of the virus our research provides data that may explain the beneficial effects of R. japonica on COVID-19 and identify the most active compounds worthy of more extensive research.<\/jats:p>","DOI":"10.3390\/ph14080742","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T21:21:21Z","timestamp":1627593681000},"page":"742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Reynoutria Rhizomes as a Natural Source of SARS-CoV-2 Mpro Inhibitors\u2013Molecular Docking and In Vitro Study"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-7336","authenticated-orcid":false,"given":"Izabela","family":"Nawrot-Hadzik","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biology and Botany, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-9160","authenticated-orcid":false,"given":"Mikolaj","family":"Zmudzinski","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7283-2653","authenticated-orcid":false,"given":"Adam","family":"Matkowski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology and Botany, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Preissner","sequence":"additional","affiliation":[{"name":"Structural Bioinformatics Group, Institute for Physiology, Charit\u00e9\u2013University Medicine Berlin, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"K\u0119sik-Brodacka","sequence":"additional","affiliation":[{"name":"Research Network \u0141ukasiewicz\u2014Institute of Biotechnology and Antibiotics, Staro\u015bci\u0144ska 5, 02-516 Warsaw, Poland"},{"name":"National Medicines Institute, ul. Che\u0142mska 30\/34, 00-725 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2353-3198","authenticated-orcid":false,"given":"Jakub","family":"Hadzik","sequence":"additional","affiliation":[{"name":"Department of Dental Surgery, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8510-1967","authenticated-orcid":false,"given":"Marcin","family":"Drag","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-8078","authenticated-orcid":false,"given":"Renata","family":"Abel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology and Botany, Wroclaw Medical University, 50-556 Wroclaw, Poland"},{"name":"Structural Bioinformatics Group, Institute for Physiology, Charit\u00e9\u2013University Medicine Berlin, 10115 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A novel coronavirus outbreak of global health concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eabe9403","DOI":"10.1126\/science.abe9403","article-title":"Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms","volume":"370","author":"Gordon","year":"2020","journal-title":"Science"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"5152","DOI":"10.1038\/s41467-020-18963-y","article-title":"Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness","volume":"11","author":"Pierron","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e667","DOI":"10.1016\/S2589-7500(20)30192-8","article-title":"Artificial intelligence in COVID-19 drug repurposing","volume":"2","author":"Zhou","year":"2020","journal-title":"Lancet Digit. Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Adeoye, A.O., Oso, B.J., Olaoye, I.F., Tijjani, H., and Adebayo, A.I. (2020). Repurposing of chloroquine and some clinically approved antiviral drugs as effective therapeutics to prevent cellular entry and replication of coronavirus. J. Biomol. Struct. Dyn., 1\u201311.","DOI":"10.1080\/07391102.2020.1765876"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jia, Z., Song, X., Shi, J., Wang, W., and He, K. (2020). Transcriptome-based drug repositioning for coronavirus disease 2019 (COVID-19). Pathog. Dis., 78.","DOI":"10.1093\/femspd\/ftaa036"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Khan, A., Ali, S.S., Khan, M.T., Saleem, S., Ali, A., Suleman, M., Babar, Z., Shafiq, A., Khan, M., and Wei, D.-Q. (2020). Combined drug repurposing and virtual screening strategies with molecular dynamics simulation identified potent inhibitors for SARS-CoV-2 main protease (3CLpro). J. Biomol. Struct. Dyn., 1\u201312.","DOI":"10.1080\/07391102.2020.1779128"},{"key":"ref_10","unstructured":"(2021, June 10). Available online: https:\/\/go.drugbank.com\/covid-19."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2000028","DOI":"10.1002\/minf.202000028","article-title":"Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3\u2005Billion Compounds","volume":"39","author":"Ton","year":"2020","journal-title":"Mol. Inform."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.apsb.2020.02.008","article-title":"Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods","volume":"10","author":"Wu","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fchem.2020.590263","article-title":"Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2","volume":"8","author":"Abel","year":"2020","journal-title":"Front. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"583","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41589-020-00689-z","article-title":"SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging","volume":"17","author":"Rut","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vicidomini, C., Roviello, V., and Roviello, G.N. (2021). Molecular Basis of the Therapeutical Potential of Clove (Syzygium aromaticum L.) and Clues to Its Anti-COVID-19 Utility. Molecules, 26.","DOI":"10.3390\/molecules26071880"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.antiviral.2005.02.007","article-title":"Identification of natural compounds with antiviral activities against SARS-associated coronavirus","volume":"67","author":"Li","year":"2005","journal-title":"Antiviral Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Vicidomini, C., Roviello, V., and Roviello, G.N. (2021). In Silico Investigation on the Interaction of Chiral Phytochemicals from Opuntia ficus-indica with SARS-CoV-2 Mpro. Symmetry, 13.","DOI":"10.3390\/sym13061041"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.sajb.2020.07.035","article-title":"Identification of potential SARS-CoV-2 inhibitors from South African medicinal plant extracts using molecular modelling approaches","volume":"133","author":"Dwarka","year":"2020","journal-title":"S. Afr. J. Bot."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.3389\/fphar.2020.561334","article-title":"Anti-SARS-CoV Natural Products With the Potential to Inhibit SARS-CoV-2 (COVID-19)","volume":"11","author":"Verma","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128823","DOI":"10.1016\/j.molstruc.2020.128823","article-title":"Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein","volume":"1221","author":"Kulkarni","year":"2020","journal-title":"J. Mol. Struct."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Shree, P., Mishra, P., Selvaraj, C., Singh, S.K., Chaube, R., Garg, N., and Tripathi, Y.B. (2020). Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of ayurvedic medicinal plants\u2014Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi)\u2014A molecular docking study. J. Biomol. Struct. Dyn., 1\u201314.","DOI":"10.1080\/07391102.2020.1810778"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.jep.2013.05.007","article-title":"Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb.et Zucc.: A review","volume":"148","author":"Peng","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5582\/bst.8.45","article-title":"Shufeng Jiedu Capsule protect against acute lung injury by suppressing the MAPK\/NF-\u03baB pathway","volume":"8","author":"Tao","year":"2014","journal-title":"Biosci. Trends"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1021\/acs.jproteome.7b00409","article-title":"Therapeutic Mechanistic Studies of ShuFengJieDu Capsule in an Acute Lung Injury Animal Model Using Quantitative Proteomics Technology","volume":"16","author":"Tao","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.apsb.2020.05.007","article-title":"Analysis on herbal medicines utilized for treatment of COVID-19","volume":"10","author":"Luo","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.5582\/bst.2020.01030","article-title":"Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment","volume":"14","author":"Wang","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref_28","first-page":"3225","article-title":"Stilbene-based natural compounds as promising drug candidates against COVID-19","volume":"39","author":"Wahedi","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.antiviral.2006.04.014","article-title":"Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction","volume":"74","author":"Ho","year":"2007","journal-title":"Antiviral Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Muchtaridi, M., Fauzi, M., Ikram, N.K.K., Gazzali, A.M., and Wahab, H.A. (2020). Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2. Molecules, 25.","DOI":"10.3390\/molecules25173980"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Maroli, N., Bhasuran, B., Natarajan, J., and Kolandaivel, P. (2020). The potential role of procyanidin as a therapeutic agent against SARS-CoV-2: A text mining, molecular docking and molecular dynamics simulation approach. J. Biomol. Struct. Dyn., 1\u201316.","DOI":"10.26434\/chemrxiv.12579599"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1055\/a-0605-3857","article-title":"Isolation and Determination of Phenolic Glycosides and Anthraquinones from Rhizomes of Various Reynoutria Species","volume":"84","author":"Granica","year":"2018","journal-title":"Planta Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nawrot-Hadzik, I., Slusarczyk, S., Granica, S., Hadzik, J., and Matkowski, A. (2019). Phytochemical diversity in rhizomes of three Reynoutria species and their antioxidant activity correlations elucidated by LC-ESI-MS\/MS analysis. Molecules, 24.","DOI":"10.20944\/preprints201902.0242.v1"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nawrot-Hadzik, I., Choroma\u0144ska, A., Abel, R., Preissner, R., Saczko, J., Matkowski, A., and Hadzik, J. (2020). Cytotoxic effect of vanicosides a and b from reynoutria sachalinensis against melanotic and amelanotic melanoma cell lines and in silico evaluation for inhibition of brafv600e and mek1. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134611"},{"key":"ref_35","first-page":"1","article-title":"An update on oligosaccharides and their esters from traditional Chinese medicines: Chemical structures and biological activities","volume":"2015","author":"Chen","year":"2015","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.biochi.2005.10.001","article-title":"Procyanidin structure defines the extent and specificity of angiotensin I converting enzyme inhibition","volume":"88","author":"Ottaviani","year":"2006","journal-title":"Biochimie"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.foodchem.2015.04.144","article-title":"The complexity of condensed tannin binding to bovine serum albumin\u2014An isothermal titration calorimetry study","volume":"190","author":"Kilmister","year":"2016","journal-title":"Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108999","DOI":"10.1016\/j.biopha.2019.108999","article-title":"Proanthocyanidins: A comprehensive review","volume":"116","author":"Rauf","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.antiviral.2009.02.001","article-title":"Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection","volume":"82","author":"Zhuang","year":"2009","journal-title":"Antiviral Res."},{"key":"ref_40","unstructured":"Conzelmann, C., Weil, T., Gross, R., Jungke, P., Frank, B., Eggers, M., Mueller, J.A., and Muench, J. (2020). Antiviral activity of plant juices and green tea against SARS-CoV-2 and influenza virus in vitro. bioRxiv."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sidor, A., and Gramza-Micha\u0142owska, A. (2019). Black Chokeberry Aronia Melanocarpa L.\u2014A Qualitative Composition, Phenolic Profile and Antioxidant Potential. Molecules, 24.","DOI":"10.3390\/molecules24203710"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jep.2016.05.016","article-title":"Antiviral activity of hydroalcoholic extract from Eupatorium perfoliatum L. Against the attachment of influenza A virus","volume":"188","author":"Derksen","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","first-page":"3330","article-title":"Pretreatment with a grape seed proanthocyanidin extract downregulates proinflammatory cytokine expression in airway epithelial cells infected with respiratory syncytial virus","volume":"19","author":"Kim","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Derksen, A., Hensel, A., Hafezi, W., Herrmann, F., Schmidt, T.J., Ehrhardt, C., Ludwig, S., and K\u00fchn, J. (2014). 3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110089"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.antiviral.2010.10.007","article-title":"Oligomeric proanthocyanidins from Rumex acetosa L. inhibit the attachment of herpes simplex virus type-1","volume":"89","author":"Gescher","year":"2011","journal-title":"Antiviral Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/hep.28952","article-title":"A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins","volume":"65","author":"Tsukuda","year":"2017","journal-title":"Hepatology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1055\/a-1177-4396","article-title":"Challenges at the Time of COVID-19: Opportunities and Innovations in Antivirals from Nature","volume":"86","author":"Hensel","year":"2020","journal-title":"Planta Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"577442","DOI":"10.3389\/fimmu.2020.577442","article-title":"Immunomodulation for Severe COVID-19 Pneumonia: The State of the Art","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"104939","DOI":"10.1016\/j.phrs.2020.104939","article-title":"Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19)","volume":"158","author":"Huang","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_50","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 1 1Edited by F. E. Cohen","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_53","first-page":"D1388","article-title":"PubChem in 2021: New data content and improved web interfaces","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_54","unstructured":"(2020, January 15). Dassault Syst\u00e8mes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego- Dassault Syst\u00e8mes. Available online: https:\/\/discover.3ds.com\/discovery-studio-visualizer-download."},{"key":"ref_55","unstructured":"(2020, July 31). The PyMOL Molecular Graphics System. Available online: Citeulike-article-id:240061%5Cnhttp:\/\/www.pymol.org."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zmudzinski, M., Rut, W., Olech, K., Granda, J., Giurg, M., Burda-Grabowska, M., Zhang, L., Sun, X., Lv, Z., and Nayak, D. (2020). Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases\u2014PLpro and Mpro in in vitro studies. bioRxiv.","DOI":"10.1101\/2020.08.30.273979"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:36:36Z","timestamp":1760164596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/8\/742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ph14080742"],"URL":"https:\/\/doi.org\/10.3390\/ph14080742","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]}}}