{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:05:49Z","timestamp":1778673949509,"version":"3.51.4"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]},{"name":"The Ministry of Science and ICT, Republic of Korea","award":["2019R1A2C2005492"],"award-info":[{"award-number":["2019R1A2C2005492"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pandemic caused by severe acute respiratory Coronavirus-2 (SARS-CoV-2) has been ongoing for over two years, and treatment for COVID-19, other than monoclonal antibodies, is urgently required. Accordingly, we have investigated the inhibitors of SARS-CoV-2 protein targets by high-throughput virtual screening using a marine natural products database. Considering the calculated molecular properties and availability of the compounds, (+)-usnic acid was selected as a suitable hit. In the in vitro antiviral assay of (+)-usnic acid by the immunofluorescence method, IC<jats:sub>50<\/jats:sub> was 7.99\u00a0\u03bcM, which is similar to that of remdesivir used as a positive control. The generalized Born and surface area continuum solvation (MM\/GBSA) method was performed to find the potent target of (+)-usnic acid, and the Mpro protein showed the most prominent value, \u221252.05\u00a0kcal\/mol, among other SARS-CoV-2 protein targets. Thereafter, RMSD and protein\u2013ligand interactions were profiled using molecular dynamics (MD) simulations. Sodium usnate (NaU) improved in vitro assay results with an IC<jats:sub>50<\/jats:sub> of 5.33\u00a0\u03bcM and a selectivity index (SI) of 9.38. Additionally, when (+)-usnic acid was assayed against SARS-CoV-2 variants, it showed enhanced efficacy toward beta variants with an IC<jats:sub>50<\/jats:sub> of 2.92\u00a0\u03bcM and SI of 11.1. We report the in vitro anti-SARS-CoV-2 efficacy of (+)-usnic acid in this study and propose that it has the potential to be developed as a COVID-19 treatment if its in vivo efficacy has been confirmed.<\/jats:p>","DOI":"10.1038\/s41598-022-17506-3","type":"journal-article","created":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T09:14:38Z","timestamp":1659172478000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["(+)-Usnic acid and its salts, inhibitors of SARS\u2010CoV\u20102, identified by using in silico methods and in vitro assay"],"prefix":"10.1038","volume":"12","author":[{"given":"Eunseok","family":"Oh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyu-Hyung","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanyoon","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youbin","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JunI","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunmo","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heonjoong","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,30]]},"reference":[{"key":"17506_CR1","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","volume":"19","author":"WT Harvey","year":"2021","unstructured":"Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409\u2013424. https:\/\/doi.org\/10.1038\/s41579-021-00573-0 (2021).","journal-title":"Nat. Rev. Microbiol."},{"key":"17506_CR2","unstructured":"WHO. WHO Coronavirus (COVID-19) Dashboard. https:\/\/covid19.who.int\/ (2021)."},{"key":"17506_CR3","doi-asserted-by":"crossref","unstructured":"Ruan, L. & Zeng, G. in Emerging Infections in Asia, 75\u201396 (Springer, 2008).","DOI":"10.1007\/978-0-387-75722-3_5"},{"key":"17506_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3201\/eid2207.160022","volume":"22","author":"TM Uyeki","year":"2016","unstructured":"Uyeki, T. M. et al. Development of Medical Countermeasures to Middle East Respiratory Syndrome Coronavirus. Emerg. Infect. Dis. 22, 1. https:\/\/doi.org\/10.3201\/eid2207.160022 (2016).","journal-title":"Emerg. Infect. Dis."},{"key":"17506_CR5","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.it.2020.10.004","volume":"41","author":"AG Harrison","year":"2020","unstructured":"Harrison, A. G., Lin, T. & Wang, P. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends Immunol. 41, 1100\u20131115. https:\/\/doi.org\/10.1016\/j.it.2020.10.004 (2020).","journal-title":"Trends Immunol."},{"key":"17506_CR6","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1016\/j.tibs.2021.06.001","volume":"46","author":"R Peng","year":"2021","unstructured":"Peng, R., Wu, L. A., Wang, Q., Qi, J. & Gao, G. F. Cell entry by SARS-CoV-2. Trends Biochem. Sci. 46, 848\u2013860. https:\/\/doi.org\/10.1016\/j.tibs.2021.06.001 (2021).","journal-title":"Trends Biochem. Sci."},{"key":"17506_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x","author":"CB Jackson","year":"2021","unstructured":"Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. https:\/\/doi.org\/10.1038\/s41580-021-00418-x (2021).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"17506_CR8","doi-asserted-by":"publisher","first-page":"11727","DOI":"10.1073\/pnas.2003138117","volume":"117","author":"J Shang","year":"2020","unstructured":"Shang, J. et al. Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. USA 117, 11727\u201311734. https:\/\/doi.org\/10.1073\/pnas.2003138117 (2020).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"17506_CR9","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2168","volume":"31","author":"S Li","year":"2021","unstructured":"Li, S. et al. SARS-CoV-2: Mechanism of infection and emerging technologies for future prospects. Rev. Med. Virol. 31, e2168 (2021).","journal-title":"Rev. Med. Virol."},{"key":"17506_CR10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","volume":"19","author":"P V'Kovski","year":"2021","unstructured":"V\u2019Kovski, P., Kratzel, A., Steiner, S., Stalder, H. & Thiel, V. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol. 19, 155\u2013170. https:\/\/doi.org\/10.1038\/s41579-020-00468-6 (2021).","journal-title":"Nat. Rev. Microbiol."},{"key":"17506_CR11","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1042\/BCJ20200029","volume":"477","author":"B Krichel","year":"2020","unstructured":"Krichel, B., Falke, S., Hilgenfeld, R., Redecke, L. & Uetrecht, C. Processing of the SARS-CoV pp1a\/ab nsp7-10 region. Biochem. J. 477, 1009\u20131019. https:\/\/doi.org\/10.1042\/BCJ20200029 (2020).","journal-title":"Biochem. J."},{"key":"17506_CR12","first-page":"1","volume":"1","author":"AR Fehr","year":"2015","unstructured":"Fehr, A. R. & Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. Coronaviruses 1, 1\u201323 (2015).","journal-title":"Coronaviruses"},{"key":"17506_CR13","doi-asserted-by":"publisher","first-page":"5885","DOI":"10.1038\/s41467-020-19619-7","volume":"11","author":"S Klein","year":"2020","unstructured":"Klein, S. et al. SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat. Commun. 11, 5885. https:\/\/doi.org\/10.1038\/s41467-020-19619-7 (2020).","journal-title":"Nat. Commun."},{"key":"17506_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells10030503","volume":"10","author":"J Saraste","year":"2021","unstructured":"Saraste, J. & Prydz, K. Assembly and cellular exit of coronaviruses: Hijacking an unconventional secretory pathway from the pre-golgi intermediate compartment via the golgi ribbon to the extracellular space. Cells 10, 1. https:\/\/doi.org\/10.3390\/cells10030503 (2021).","journal-title":"Cells"},{"key":"17506_CR15","doi-asserted-by":"publisher","unstructured":"Yang, T. J. et al. Effect of SARS-CoV-2 B.1.1.7 mutations on spike protein structure and function. Nat Struct Mol Biol 28, 731\u2013739, doi:https:\/\/doi.org\/10.1038\/s41594-021-00652-z (2021).","DOI":"10.1038\/s41594-021-00652-z"},{"key":"17506_CR16","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.3390\/w13182503","volume":"13","author":"G La Rosa","year":"2021","unstructured":"La Rosa, G. et al. Key SARS-CoV-2 mutations of alpha, gamma, and eta variants detected in urban wastewaters in Italy by long-read amplicon sequencing based on nanopore technology. Water 13, 2503 (2021).","journal-title":"Water"},{"key":"17506_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-26401-w","volume":"12","author":"P Han","year":"2021","unstructured":"Han, P. et al. Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants. Nat. Commun. 12, 1\u20139 (2021).","journal-title":"Nat. Commun."},{"key":"17506_CR18","doi-asserted-by":"publisher","unstructured":"Haque, S. M., Ashwaq, O., Sarief, A. & Azad John Mohamed, A. K. A comprehensive review about SARS-CoV-2. Future Virol 15, 625\u2013648. https:\/\/doi.org\/10.2217\/fvl-2020-0124 (2020).","DOI":"10.2217\/fvl-2020-0124"},{"key":"17506_CR19","doi-asserted-by":"publisher","first-page":"16119","DOI":"10.1073\/pnas.0805240105","volume":"105","author":"K Ratia","year":"2008","unstructured":"Ratia, K. et al. A noncovalent class of papain-like protease\/deubiquitinase inhibitors blocks SARS virus replication. Proc. Natl. Acad. Sci. USA 105, 16119\u201316124. https:\/\/doi.org\/10.1073\/pnas.0805240105 (2008).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"17506_CR20","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41467-020-20718-8","volume":"12","author":"Z Fu","year":"2021","unstructured":"Fu, Z. et al. The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery. Nat. Commun. 12, 488. https:\/\/doi.org\/10.1038\/s41467-020-20718-8 (2021).","journal-title":"Nat. Commun."},{"key":"17506_CR21","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1126\/science.abf1611","volume":"371","author":"J Qiao","year":"2021","unstructured":"Qiao, J. et al. SARS-CoV-2 M(pro) inhibitors with antiviral activity in a transgenic mouse model. Science 371, 1374\u20131378. https:\/\/doi.org\/10.1126\/science.abf1611 (2021).","journal-title":"Science"},{"key":"17506_CR22","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/s41467-020-20542-0","volume":"12","author":"G Kokic","year":"2021","unstructured":"Kokic, G. et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat. Commun. 12, 279. https:\/\/doi.org\/10.1038\/s41467-020-20542-0 (2021).","journal-title":"Nat. Commun."},{"key":"17506_CR23","doi-asserted-by":"publisher","first-page":"4848","DOI":"10.1038\/s41467-021-25166-6","volume":"12","author":"JA Newman","year":"2021","unstructured":"Newman, J. A. et al. Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase. Nat. Commun. 12, 4848. https:\/\/doi.org\/10.1038\/s41467-021-25166-6 (2021).","journal-title":"Nat. Commun."},{"key":"17506_CR24","doi-asserted-by":"publisher","first-page":"10290","DOI":"10.1038\/s41598-021-89724-0","volume":"11","author":"SH Abidi","year":"2021","unstructured":"Abidi, S. H. et al. Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase. Sci. Rep. 11, 10290. https:\/\/doi.org\/10.1038\/s41598-021-89724-0 (2021).","journal-title":"Sci. Rep."},{"key":"17506_CR25","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1021\/acsinfecdis.0c00701","volume":"7","author":"T Tang","year":"2021","unstructured":"Tang, T. et al. Proteolytic activation of SARS-CoV-2 spike at the S1\/S2 boundary: Potential role of proteases beyond Furin. ACS Infect Dis 7, 264\u2013272. https:\/\/doi.org\/10.1021\/acsinfecdis.0c00701 (2021).","journal-title":"ACS Infect Dis"},{"key":"17506_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108254","volume":"33","author":"YW Cheng","year":"2020","unstructured":"Cheng, Y. W. et al. Furin inhibitors block SARS-CoV-2 spike protein cleavage to suppress virus production and cytopathic effects. Cell Rep. 33, 108254. https:\/\/doi.org\/10.1016\/j.celrep.2020.108254 (2020).","journal-title":"Cell Rep."},{"key":"17506_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103255","volume":"65","author":"M Hoffmann","year":"2021","unstructured":"Hoffmann, M. et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine 65, 103255. https:\/\/doi.org\/10.1016\/j.ebiom.2021.103255 (2021).","journal-title":"EBioMedicine"},{"key":"17506_CR28","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.antiviral.2015.01.011","volume":"116","author":"Y Zhou","year":"2015","unstructured":"Zhou, Y. et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 116, 76\u201384. https:\/\/doi.org\/10.1016\/j.antiviral.2015.01.011 (2015).","journal-title":"Antiviral Res."},{"key":"17506_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.100849","volume":"35","author":"JD Gunst","year":"2021","unstructured":"Gunst, J. D. et al. Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial. EClinicalMedicine 35, 100849. https:\/\/doi.org\/10.1016\/j.eclinm.2021.100849 (2021).","journal-title":"EClinicalMedicine"},{"key":"17506_CR30","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/s41392-021-00558-8","volume":"6","author":"MM Zhao","year":"2021","unstructured":"Zhao, M. M. et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal Transduct. Target Ther. 6, 134. https:\/\/doi.org\/10.1038\/s41392-021-00558-8 (2021).","journal-title":"Signal Transduct. Target Ther."},{"key":"17506_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.589505","volume":"10","author":"CP Gomes","year":"2020","unstructured":"Gomes, C. P. et al. Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics. Front. Cell Infect. Microbiol. 10, 589505. https:\/\/doi.org\/10.3389\/fcimb.2020.589505 (2020).","journal-title":"Front. Cell Infect. Microbiol."},{"key":"17506_CR32","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","volume":"11","author":"X Ou","year":"2020","unstructured":"Ou, X. et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 11, 1620. https:\/\/doi.org\/10.1038\/s41467-020-15562-9 (2020).","journal-title":"Nat. Commun."},{"key":"17506_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00331-3","author":"VC Marconi","year":"2021","unstructured":"Marconi, V. C. et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir. Med. https:\/\/doi.org\/10.1016\/S2213-2600(21)00331-3 (2021).","journal-title":"Lancet Respir. Med."},{"key":"17506_CR34","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","volume":"83","author":"DJ Newman","year":"2020","unstructured":"Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019. J. Nat. Prod. 83, 770\u2013803 (2020).","journal-title":"J. Nat. Prod."},{"key":"17506_CR35","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.sajb.2021.03.012","volume":"139","author":"AG Omokhua-Uyi","year":"2021","unstructured":"Omokhua-Uyi, A. G. & Van Staden, J. Natural product remedies for COVID-19: A focus on safety. S. Afr. J. Bot. 139, 386\u2013398. https:\/\/doi.org\/10.1016\/j.sajb.2021.03.012 (2021).","journal-title":"S. Afr. J. Bot."},{"key":"17506_CR36","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13321-020-00424-9","volume":"12","author":"M Sorokina","year":"2020","unstructured":"Sorokina, M. & Steinbeck, C. Review on natural products databases: where to find data in 2020. J. Cheminform. 12, 20. https:\/\/doi.org\/10.1186\/s13321-020-00424-9 (2020).","journal-title":"J. Cheminform."},{"key":"17506_CR37","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1039\/d0np00089b","volume":"38","author":"AR Carroll","year":"2021","unstructured":"Carroll, A. R., Copp, B. R., Davis, R. A., Keyzers, R. A. & Prinsep, M. R. Marine natural products. Nat. Prod. Rep. 38, 362\u2013413. https:\/\/doi.org\/10.1039\/d0np00089b (2021).","journal-title":"Nat. Prod. Rep."},{"key":"17506_CR38","doi-asserted-by":"publisher","first-page":"24","DOI":"10.4103\/2225-4110.124335","volume":"4","author":"LT Lin","year":"2014","unstructured":"Lin, L. T., Hsu, W. C. & Lin, C. C. Antiviral natural products and herbal medicines. J. Tradit. Complement Med. 4, 24\u201335. https:\/\/doi.org\/10.4103\/2225-4110.124335 (2014).","journal-title":"J. Tradit. Complement Med."},{"key":"17506_CR39","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1002\/ptr.6614","volume":"34","author":"JK Patra","year":"2020","unstructured":"Patra, J. K. et al. Star anise (Illicium verum): Chemical compounds, antiviral properties, and clinical relevance. Phytother. Res. 34, 1248\u20131267. https:\/\/doi.org\/10.1002\/ptr.6614 (2020).","journal-title":"Phytother. Res."},{"key":"17506_CR40","unstructured":"Schr\u00f6dinger Release\u00a02021\u20133: LigPrep, Schr\u00f6dinger, LLC, New York, NY, (2021)."},{"key":"17506_CR41","unstructured":"Schr\u00f6dinger Release\u00a02021\u20133: Glide, Schr\u00f6dinger, LLC, New York, NY, (2021)."},{"key":"17506_CR42","unstructured":"Schr\u00f6dinger Release\u00a02021\u20133: QikProp, Schr\u00f6dinger, LLC, New York, NY, (2021)."},{"key":"17506_CR43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.abd4596","volume":"6","author":"W Rut","year":"2020","unstructured":"Rut, W. et al. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design. Sci. Adv. 6, 1. https:\/\/doi.org\/10.1126\/sciadv.abd4596 (2020).","journal-title":"Sci. Adv."},{"key":"17506_CR44","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1126\/science.abf7945","volume":"372","author":"S Gunther","year":"2021","unstructured":"Gunther, S. et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science 372, 642\u2013646. https:\/\/doi.org\/10.1126\/science.abf7945 (2021).","journal-title":"Science"},{"key":"17506_CR45","doi-asserted-by":"publisher","first-page":"12493","DOI":"10.1038\/s41598-020-69337-9","volume":"10","author":"R Yoshino","year":"2020","unstructured":"Yoshino, R., Yasuo, N. & Sekijima, M. Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates. Sci. Rep. 10, 12493. https:\/\/doi.org\/10.1038\/s41598-020-69337-9 (2020).","journal-title":"Sci. Rep."},{"key":"17506_CR46","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1126\/science.abc1560","volume":"368","author":"W Yin","year":"2020","unstructured":"Yin, W. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science 368, 1499\u20131504. https:\/\/doi.org\/10.1126\/science.abc1560 (2020).","journal-title":"Science"},{"key":"17506_CR47","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1021\/acs.biochem.7b01124","volume":"57","author":"SO Dahms","year":"2018","unstructured":"Dahms, S. O., Hardes, K., Steinmetzer, T. & Than, M. E. X-ray structures of the proprotein convertase furin bound with substrate analogue inhibitors reveal substrate specificity determinants beyond the S4 Pocket. Biochemistry 57, 925\u2013934. https:\/\/doi.org\/10.1021\/acs.biochem.7b01124 (2018).","journal-title":"Biochemistry"},{"key":"17506_CR48","doi-asserted-by":"publisher","first-page":"350","DOI":"10.3934\/microbiol.2020021","volume":"6","author":"M Hussain","year":"2020","unstructured":"Hussain, M. et al. Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: Conformation and intermolecular interactions. AIMS Microbiol 6, 350\u2013360. https:\/\/doi.org\/10.3934\/microbiol.2020021 (2020).","journal-title":"AIMS Microbiol"},{"key":"17506_CR49","doi-asserted-by":"publisher","unstructured":"Chowdhury, S. F. et al. Design of noncovalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides. J Med Chem 45, 5321\u20135329, https:\/\/doi.org\/10.1021\/jm020238t (2002).","DOI":"10.1021\/jm020238t"},{"key":"17506_CR50","doi-asserted-by":"publisher","unstructured":"Sorrell, F. J., Szklarz, M., Abdul Azeez, K. R., Elkins, J. M. & Knapp, S. Family-wide Structural Analysis of Human Numb-Associated Protein Kinases. Structure 24, 401\u2013411, doi:https:\/\/doi.org\/10.1016\/j.str.2015.12.015 (2016).","DOI":"10.1016\/j.str.2015.12.015"},{"key":"17506_CR51","unstructured":"Schr\u00f6dinger Release 2021\u20133: Prime, Schr\u00f6dinger, LLC, New York, NY, 2021."},{"key":"17506_CR52","unstructured":"Bowers, K. J. et al. in SC'06: Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing. 43\u201343 (IEEE)."},{"key":"17506_CR53","unstructured":"Schr\u00f6dinger Release 2021\u20133: Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, 2021. Maestro-Desmond Interoperability Tools, Schr\u00f6dinger, New York, NY, 2021."},{"key":"17506_CR54","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/jlac.18440490202","volume":"49","author":"W Knop","year":"1844","unstructured":"Knop, W. Chemisch-physiologische Untersuchung \u00fcber die Flechten. Justus Liebigs Ann. Chem. 49, 103\u2013124 (1844).","journal-title":"Justus Liebigs Ann. Chem."},{"key":"17506_CR55","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/S0031-9422(02)00383-7","volume":"61","author":"K Ingolfsdottir","year":"2002","unstructured":"Ingolfsdottir, K. Usnic acid. Phytochemistry 61, 729\u2013736 (2002).","journal-title":"Phytochemistry"},{"key":"17506_CR56","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s11101-019-09605-3","volume":"18","author":"A Galanty","year":"2019","unstructured":"Galanty, A., Pa\u015bko, P. & Podolak, I. Enantioselective activity of usnic acid: A comprehensive review and future perspectives. Phytochem. Rev. 18, 527\u2013548. https:\/\/doi.org\/10.1007\/s11101-019-09605-3 (2019).","journal-title":"Phytochem. Rev."},{"key":"17506_CR57","doi-asserted-by":"publisher","first-page":"7060","DOI":"10.1016\/j.bmcl.2012.09.084","volume":"22","author":"DN Sokolov","year":"2012","unstructured":"Sokolov, D. N. et al. Anti-viral activity of (-)- and (+)-usnic acids and their derivatives against influenza virus A(H1N1)2009. Bioorg Med Chem Lett 22, 7060\u20137064. https:\/\/doi.org\/10.1016\/j.bmcl.2012.09.084 (2012).","journal-title":"Bioorg Med Chem Lett"},{"key":"17506_CR58","doi-asserted-by":"publisher","unstructured":"Lee, J. et al. Mycousfurans A and B, Antibacterial Usnic Acid Congeners from the Fungus Mycosphaerella sp., Isolated from a Marine Sediment. Mar Drugs 17. https:\/\/doi.org\/10.3390\/md17070422 (2019).","DOI":"10.3390\/md17070422"},{"key":"17506_CR59","doi-asserted-by":"publisher","unstructured":"Ullrich, S., Ekanayake, K. B., Otting, G. & Nitsche, C. Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir. Bioorg Med Chem Lett 62, 128629. https:\/\/doi.org\/10.1016\/j.bmcl.2022.128629 (2022)","DOI":"10.1016\/j.bmcl.2022.128629"},{"key":"17506_CR60","doi-asserted-by":"publisher","unstructured":"Sokalingam, S., Raghunathan, G., Soundrarajan, N. & Lee, S. G. A study on the effect of surface lysine to arginine mutagenesis on protein stability and structure using green fluorescent protein. PLoS One 7, e40410, doi:https:\/\/doi.org\/10.1371\/journal.pone.0040410 (2012)","DOI":"10.1371\/journal.pone.0040410"},{"key":"17506_CR61","doi-asserted-by":"crossref","unstructured":"Durazo, F. A. et al. Fulminant liver failure due to usnic acid for weight loss. Official journal of the American College of Gastroenterology| ACG 99, 950\u2013952 (2004).","DOI":"10.1111\/j.1572-0241.2004.04165.x"},{"key":"17506_CR62","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jep.2003.10.019","volume":"90","author":"P Pramyothin","year":"2004","unstructured":"Pramyothin, P., Janthasoot, W., Pongnimitprasert, N., Phrukudom, S. & Ruangrungsi, N. Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. J. Ethnopharmacol. 90, 381\u2013387. https:\/\/doi.org\/10.1016\/j.jep.2003.10.019 (2004).","journal-title":"J. Ethnopharmacol."},{"key":"17506_CR63","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1111\/j.1440-1746.2005.03855.x","volume":"20","author":"LM Hsu","year":"2005","unstructured":"Hsu, L. M., Huang, Y. S., Chang, F. Y. & Lee, S. D. \u201cFat burner\u201d herb, usnic acid, induced acute hepatitis in a family. J. Gastroenterol. Hepatol. 20, 1138\u20131139. https:\/\/doi.org\/10.1111\/j.1440-1746.2005.03855.x (2005).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"17506_CR64","doi-asserted-by":"publisher","first-page":"16234","DOI":"10.1038\/s41598-018-34709-9","volume":"8","author":"Y Yang","year":"2018","unstructured":"Yang, Y. et al. Potassium usnate, a water-soluble usnic acid salt, shows enhanced bioavailability and inhibits invasion and metastasis in colorectal cancer. Sci. Rep. 8, 16234. https:\/\/doi.org\/10.1038\/s41598-018-34709-9 (2018).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17506-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17506-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17506-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T05:02:31Z","timestamp":1669352551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-17506-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,30]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["17506"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-17506-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,30]]},"assertion":[{"value":"15 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13118"}}