{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:16:49Z","timestamp":1790335009611,"version":"4.1.0"},"reference-count":50,"publisher":"American Chemical Society (ACS)","issue":"11","license":[{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-001"},{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-009"},{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the death of more than 675,000 worldwide and over 150,000 in the United States alone. However, there are currently no approved effective pharmacotherapies for COVID-19. Here, we combine homology modeling, molecular docking, molecular dynamics simulation, and binding affinity calculations to determine potential targets for toremifene, a selective estrogen receptor modulator which we have previously identified as a SARS-CoV-2 inhibitor. Our results indicate the possibility of inhibition of the spike glycoprotein by toremifene, responsible for aiding in fusion of the viral membrane with the cell membrane, via a perturbation to the fusion core. An interaction between the dimethylamine end of toremifene and residues Q954 and N955 in heptad repeat 1 (HR1) perturbs the structure, causing a shift from what is normally a long, helical region to short helices connected by unstructured regions. Additionally, we found a strong interaction between toremifene and the methyltransferase nonstructural protein (NSP) 14, which could be inhibitory to viral replication via its active site. These results suggest potential structural mechanisms for toremifene by blocking the spike protein and NSP14 of SARS-CoV-2, offering a drug candidate for COVID-19.<\/jats:p>","DOI":"10.1021\/acs.jproteome.0c00397","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T01:48:00Z","timestamp":1599702480000},"page":"4670-4677","source":"Crossref","is-referenced-by-count":58,"title":["Repurposing of\nFDA-Approved Toremifene to Treat COVID-19\nby Blocking the Spike Glycoprotein and NSP14 of SARS-CoV\u20112"],"prefix":"10.1021","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-0462","authenticated-orcid":true,"given":"William\nR.","family":"Martin","sequence":"first","affiliation":[{"name":"Cleveland Clinic , , , ,","place":["Cleveland, Ohio, United States, 44195"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-2847","authenticated-orcid":true,"given":"Feixiong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Cleveland Clinic , , , ,","place":["Cleveland, Ohio, United States, 44195"]},{"name":"Case Western Reserve University , , , ,","place":["Cleveland, Ohio, United States, 44195"]},{"name":"Case Western Reserve University School of Medicine , , , ,","place":["Cleveland, Ohio, United States, 44106"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,9,10]]},"reference":[{"issue":"5","key":"2026081714261490200_cit1","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19\nin real time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. Dis."},{"issue":"11","key":"2026081714261490200_cit2","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/j.molmed.2016.09.006","article-title":"Drug repurposing:\nNew treatments\nfor Zika virus infection?","volume":"22","author":"Cheng","year":"2016","journal-title":"Trends Mol. Med."},{"issue":"9","key":"2026081714261490200_cit3","doi-asserted-by":"crossref","first-page":"e1005074","DOI":"10.1371\/journal.pcbi.1005074","article-title":"Systems biology-based investigation\nof cellular antiviral drug targets identified by gene-trap insertional\nmutagenesis","volume":"12","author":"Cheng","year":"2016","journal-title":"PLOS Comput. Biol."},{"issue":"1","key":"2026081714261490200_cit4","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-based\ndrug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discovery"},{"issue":"8","key":"2026081714261490200_cit5","doi-asserted-by":"publisher","first-page":"4885","DOI":"10.1128\/AAC.03036-14","article-title":"Repurposing\nof clinically\ndeveloped drugs for treatment of Middle East respiratory syndrome\ncoronavirus infection","volume":"58","author":"Dyall","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"issue":"190","key":"2026081714261490200_cit6","doi-asserted-by":"publisher","first-page":"190ra79","DOI":"10.1126\/scitranslmed.3005471","article-title":"FDA-approved selective\nestrogen receptor modulators inhibit ebola virus infection","volume":"5","author":"Johansen","year":"2013","journal-title":"Sci. Transl. Med."},{"issue":"7610","key":"2026081714261490200_cit7","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/nature18615","article-title":"Toremifene\ninteracts with and destabilizes\nthe Ebola virus glycoprotein","volume":"535","author":"Zhao","year":"2016","journal-title":"Nature"},{"key":"2026081714261490200_cit8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/2020.04.13.039917","article-title":"Human organs-on-chips\nas tools for repurposing approved\ndrugs as potential influenza and COVID19 therapeutics in viral pandemics","author":"Si","year":"2020","journal-title":"bioRxiv"},{"key":"2026081714261490200_cit9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AAC.00819-20","article-title":"Identification\nof antiviral drug candidates against\nSARS-CoV-2 from FDA-approved drugs","author":"Jeon","year":"2020","journal-title":"Antimicrob.\nAgents Chemother."},{"key":"2026081714261490200_cit10","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.jpha.2020.03.009","article-title":"Structural\nbasis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal\nplants","volume":"10","author":"Tahir\nul Qamar","year":"2020","journal-title":"J. Pharm. Anal."},{"key":"2026081714261490200_cit11","doi-asserted-by":"publisher","first-page":"129","DOI":"10.12688\/f1000research.22457.1","article-title":"Prediction of the\nSARS-CoV-2 (2019-nCoV)\n3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir,\nledipasvir, and other drug repurposing candidates","volume":"9","author":"Chen","year":"2020","journal-title":"F1000Research"},{"key":"2026081714261490200_cit12","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-based\ndesign of antiviral\ndrug candidates targeting the SARS-CoV-2 main protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"2026081714261490200_cit13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.26434\/chemrxiv.11860011.v2","article-title":"Potential inhibitors against papain-like\nprotease of novel coronavirus (SARS-CoV-2) from FDA approved drugs","author":"Arya","year":"2020","journal-title":"ChemRxiv"},{"issue":"7","key":"2026081714261490200_cit14","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1021\/ci3001277","article-title":"ZINC: A\nfree tool to discover chemistry for biology","volume":"52","author":"Irwin","year":"2012","journal-title":"J. Chem. Inf. Model."},{"issue":"23","key":"2026081714261490200_cit15","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1056\/NEJMcibr2007042","article-title":"How to discover\nantiviral drugs quickly","volume":"382","author":"Parks","year":"2020","journal-title":"N. Engl. J. Med."},{"issue":"17","key":"2026081714261490200_cit16","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST:\na new generation of protein database search programs","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"2026081714261490200_cit17","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\ue5f8A\nvisualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2026081714261490200_cit18","doi-asserted-by":"publisher","first-page":"5.6.1","DOI":"10.1002\/0471250953.bi0506s15","article-title":"Comparative protein\nstructure modeling using modeller","volume":"15","author":"Eswar","year":"2006","journal-title":"Curr. Protoc.\nBioinforma."},{"issue":"5","key":"2026081714261490200_cit19","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1110\/ps.041253405","article-title":"All are not equal: A benchmark of different homology\nmodeling programs","volume":"14","author":"Wallner","year":"2005","journal-title":"Protein Sci."},{"key":"2026081714261490200_cit20","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX."},{"issue":"9","key":"2026081714261490200_cit21","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the Additive CHARMM All-Atom\nProtein Force Field Targeting Improved Sampling of the Backbone \u03d5,\n\u03c8 and Side-Chain \u03c7 1 and \u03c7 2 Dihedral Angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"issue":"1","key":"2026081714261490200_cit22","doi-asserted-by":"publisher","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\nAcids Res."},{"issue":"2","key":"2026081714261490200_cit23","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of\ndocking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"issue":"21","key":"2026081714261490200_cit24","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1002\/jcc.24829","article-title":"CHARMM-GUI\nligand reader and modeler for CHARMM force field generation of small\nmolecules","volume":"38","author":"Kim","year":"2017","journal-title":"J. Comput. Chem."},{"issue":"1","key":"2026081714261490200_cit25","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI Input Generator\nfor NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM Simulations Using\nthe CHARMM36 Additive Force Field","volume":"12","author":"Lee","year":"2016","journal-title":"J. Chem.\nTheory Comput."},{"issue":"11","key":"2026081714261490200_cit26","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based\ngraphical\nuser interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"issue":"4","key":"2026081714261490200_cit27","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force\nfield: A force field for drug-like molecules compatible with the CHARMM\nall-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2009","journal-title":"J.\nComput. Chem."},{"issue":"12","key":"2026081714261490200_cit28","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12&lt;1463::AID-JCC4&gt;3.0.CO;2-H","article-title":"LINCS: A linear\nconstraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"issue":"13","key":"2026081714261490200_cit29","doi-asserted-by":"publisher","first-page":"134101","DOI":"10.1063\/1.2013227","article-title":"A configurational\ntemperature Nose\u0301-Hoover thermostat","volume":"123","author":"Braga","year":"2005","journal-title":"J.\nChem. Phys."},{"issue":"12","key":"2026081714261490200_cit30","doi-asserted-by":"publisher","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic\ntransitions in single crystals: A new molecular\ndynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"issue":"1","key":"2026081714261490200_cit31","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1103\/PhysRev.159.98","article-title":"Computer \u201dExperiments\u201c\non Classical Fluids. I. Thermodynamical Properties of Lennard-Jones\nMolecules","volume":"159","author":"Verlet","year":"1967","journal-title":"Phys. Rev."},{"issue":"12","key":"2026081714261490200_cit32","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh\nEwald: An N \u00b7log\u00ad(N)\nmethod for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem.\nPhys."},{"issue":"7","key":"2026081714261490200_cit33","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa \ue5f8A\nGROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"issue":"4","key":"2026081714261490200_cit34","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.cell.2020.04.011","volume":"181","author":"Kim","year":"2020","journal-title":"Cell"},{"issue":"7","key":"2026081714261490200_cit35","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1128\/JVI.01939-06","article-title":"Novel \u03b2-barrel\nfold in the nuclear magnetic resonance structure of the replicase\nnonstructural protein 1 from the severe acute respiratory syndrome\ncoronavirus","volume":"81","author":"Almeida","year":"2007","journal-title":"J. Virol."},{"issue":"7","key":"2026081714261490200_cit36","doi-asserted-by":"publisher","first-page":"e6217","DOI":"10.1371\/journal.pone.0006217","article-title":"Crystal structure of the C-terminal\ncytoplasmic domain of non-structural protein 4 from mouse hepatitis\nvirus A59","volume":"4","author":"Xu","year":"2009","journal-title":"PLoS One"},{"issue":"6492","key":"2026081714261490200_cit37","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1126\/science.abb7498","article-title":"Structure of the RNA-dependent RNA polymerase\nfrom COVID-19 virus","volume":"368","author":"Gao","year":"2020","journal-title":"Science"},{"issue":"12","key":"2026081714261490200_cit38","doi-asserted-by":"publisher","first-page":"6538","DOI":"10.1093\/nar\/gkz409","article-title":"Delicate structural coordination of the Severe\nAcute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis","volume":"47","author":"Jia","year":"2019","journal-title":"Nucleic Acids Res."},{"issue":"30","key":"2026081714261490200_cit39","doi-asserted-by":"publisher","first-page":"9436","DOI":"10.1073\/pnas.1508686112","article-title":"Structural basis and functional analysis of\nthe SARS coronavirus nsp14-nsp10 complex","volume":"112","author":"Ma","year":"2015","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"issue":"7","key":"2026081714261490200_cit40","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1002\/pro.3873","article-title":"Crystal structure of\nNsp15 endoribonuclease NendoU from SARS-CoV-2","volume":"29","author":"Kim","year":"2020","journal-title":"Protein Sci."},{"issue":"6483","key":"2026081714261490200_cit41","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of\nthe 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"2026081714261490200_cit42","doi-asserted-by":"publisher","first-page":"W270","DOI":"10.1093\/nar\/gkr366","article-title":"SwissDock,\na protein-small molecule\ndocking web service based on EADock DSS","volume":"39","author":"Grosdidier","year":"2011","journal-title":"Nucleic\nAcids Res."},{"issue":"24","key":"2026081714261490200_cit43","doi-asserted-by":"publisher","first-page":"3875","DOI":"10.1016\/j.jmb.2017.10.017","article-title":"The SARS-CoV\nfusion peptide forms an extended bipartite fusion platform that perturbs\nmembrane order in a calcium-dependent manner","volume":"429","author":"Lai","year":"2017","journal-title":"J. Mol. Biol."},{"key":"2026081714261490200_cit44","doi-asserted-by":"publisher","first-page":"41226","DOI":"10.1038\/srep41226","article-title":"Selective inhibition of Ebola entry with selective\nestrogen receptor modulators by disrupting the endolysosomal calcium","volume":"7","author":"Fan","year":"2017","journal-title":"Sci. Rep."},{"issue":"3","key":"2026081714261490200_cit45","doi-asserted-by":"publisher","first-page":"393","DOI":"10.5306\/wjco.v5.i3.393","article-title":"Toremifene in the treatment\nof breast cancer","volume":"5","author":"Mustonen","year":"2014","journal-title":"World J. Clin. Oncol."},{"issue":"1","key":"2026081714261490200_cit46","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1186\/s12885-015-1871-z","article-title":"Toremifene, a selective\nestrogen receptor modulator, significantly improved biochemical recurrence\nin bone metastatic prostate cancer: a randomized controlled phase\nII a trial","volume":"15","author":"Fujimura","year":"2015","journal-title":"BMC Cancer"},{"issue":"3","key":"2026081714261490200_cit47","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1023\/A:1005891506092","article-title":"A phase III comparison\nof two toremifene doses to tamoxifen in postmenopausal women with\nadvanced breast cancer","volume":"45","author":"Gershanovich","year":"1997","journal-title":"Breast Cancer Res. Treat."},{"issue":"10","key":"2026081714261490200_cit48","doi-asserted-by":"publisher","first-page":"4039","DOI":"10.1210\/jc.2007-0816","article-title":"Association between\nserum insulin-like growth factor-I levels and thyroid disorders in\na population-based study","volume":"92","author":"Vo\u0308lzke","year":"2007","journal-title":"J. Clin. Endocrinol.\nMetab."},{"issue":"4","key":"2026081714261490200_cit49","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/BF00684880","article-title":"Pharmacokinetics\nof toremifene and its metabolites in patients with advanced breast\ncancer","volume":"25","author":"Wiebe","year":"1990","journal-title":"Cancer Chemother. Pharmacol."},{"issue":"1","key":"2026081714261490200_cit50","doi-asserted-by":"publisher","first-page":"141","DOI":"10.2165\/00003495-199754010-00014","article-title":"Toremifene.\nA review of its pharmacological properties\nand clinical efficacy in the management of advanced breast cancer","volume":"54","author":"Wiseman","year":"1997","journal-title":"Drugs"}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.0c00397","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/19\/11\/4670\/14422136\/pr0c00397.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/19\/11\/4670\/14422136\/pr0c00397.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T18:26:22Z","timestamp":1786991182000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/19\/11\/4670\/1383532\/Repurposing-of-FDA-Approved-Toremifene-to-Treat"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,10]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,9,10]]},"published-print":{"date-parts":[[2020,11,6]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.0c00397","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv.12431966.v1","asserted-by":"object"}]},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,10]]}}}