{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T15:13:24Z","timestamp":1780586004577,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020M3A9I2081698"],"award-info":[{"award-number":["NRF-2020M3A9I2081698"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.<\/jats:p>","DOI":"10.3390\/v12111325","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T07:41:00Z","timestamp":1605685260000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Yoonjung","family":"Choi","sequence":"first","affiliation":[{"name":"Deargen, Inc., Daejeon 34051, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5133-0558","authenticated-orcid":false,"given":"Bonggun","family":"Shin","sequence":"additional","affiliation":[{"name":"Deargen, Inc., Daejeon 34051, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0611-9320","authenticated-orcid":false,"given":"Keunsoo","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan 31116, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungsoo","family":"Park","sequence":"additional","affiliation":[{"name":"Deargen, Inc., Daejeon 34051, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-3019","authenticated-orcid":false,"given":"Bo Ram","family":"Beck","sequence":"additional","affiliation":[{"name":"Deargen, Inc., Daejeon 34051, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., and Lu, R. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa2001017"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1021\/acs.jmedchem.6b01594","article-title":"Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses","volume":"60","author":"Siegel","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.dsx.2020.05.018","article-title":"Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies","volume":"14","author":"Singh","year":"2020","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.csbj.2020.03.025","article-title":"Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model","volume":"18","author":"Beck","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104786","DOI":"10.1016\/j.antiviral.2020.104786","article-title":"Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro","volume":"178","author":"Choy","year":"2020","journal-title":"Antiviral Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fintelman-Rodrigues, N., Sacramento, C.Q., Ribeiro Lima, C., Souza da Silva, F., Ferreira, A.C., Mattos, M., de Freitas, C.S., Cardoso Soares, V., da Silva Gomes Dias, S., and Temerozo, J.R. (2020). Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production. Antimicrob. Agents Chemother., 64.","DOI":"10.1128\/AAC.00825-20"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kang, K., Kim, H.H., and Choi, Y. (2020). Tiotropium is predicted to be a promising drug for COVID-19 through transcriptome-based comprehensive molecular pathway analysis. Viruses, 12.","DOI":"10.3390\/v12070776"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xiao, L., Sakagami, H., and Miwa, N. (2020). ACE2: The key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: Demon or angel?. Viruses, 12.","DOI":"10.3390\/v12050491"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/01.RES.87.5.e1","article-title":"A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9","volume":"87","author":"Donoghue","year":"2000","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.cardiores.2006.09.006","article-title":"ACE2 of the heart: From angiotensin I to angiotensin (1-7)","volume":"73","author":"Keidar","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1006\/geno.1997.4845","article-title":"Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3","volume":"44","author":"Chen","year":"1997","journal-title":"Genomics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The trinity of COVID-19: Immunity, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15 - Ligand Discovery for Everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_17","unstructured":"Shin, B., Park, S., Kang, K., and Ho, J.C. (2019). Self-Attention Based Molecule Representation for Predicting Drug-Target Interaction. arXiv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"bay083","DOI":"10.1093\/database\/bay083","article-title":"Drug Target Commons 2.0: A community platform for systematic analysis of drug-target interaction profiles","volume":"2018","author":"Tanoli","year":"2018","journal-title":"Database"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D198","DOI":"10.1093\/nar\/gkl999","article-title":"BindingDB: A web-accessible database of experimentally determined protein-ligand binding affinities","volume":"35","author":"Liu","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Oleg","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Olson AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W449","DOI":"10.1093\/nar\/gku476","article-title":"LINCS Canvas Browser: Interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures","volume":"42","author":"Duan","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Brimacombe, K.R., Zhao, T., Eastman, R.T., Hu, X., Wang, K., Backus, M., Baljinnyam, B., Chen, C.Z., Chen, L., and Eicher, T. (2020). An OpenData portal to share COVID-19 drug repurposing data in real time. bioRxiv Prepr. Serv. Biol.","DOI":"10.1101\/2020.06.04.135046"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.cell.2020.04.004","article-title":"Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2","volume":"181","author":"Monteil","year":"2020","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30113","DOI":"10.1074\/jbc.M505111200","article-title":"Tumor necrosis factor-\u03b1 convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)","volume":"280","author":"Lambert","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.febslet.2007.11.085","article-title":"Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain","volume":"582","author":"Lambert","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sonawane, K., Barale, S., Dhanavade, M., Waghmare, S., Nadaf, N., Kamble, S., Mohammed, A.A., Makandar, A., Fandilolu, P., and Dound, A. (2020). Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2. ChemRxiv.","DOI":"10.26434\/chemrxiv.12162360"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s11739-020-02345-9","article-title":"Camostat mesilate therapy for COVID-19","volume":"15","author":"Uno","year":"2020","journal-title":"Intern. Emerg. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117477","DOI":"10.1016\/j.lfs.2020.117477","article-title":"Anti-HCV, nucleotide inhibitors, repurposing against COVID-19","volume":"248","author":"Elfiky","year":"2020","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.drudis.2012.07.017","article-title":"Applications of Connectivity Map in drug discovery and development","volume":"17","author":"Qu","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"104837","DOI":"10.1016\/j.phrs.2020.104837","article-title":"Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection","volume":"157","author":"Maggio","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"100407","DOI":"10.1016\/j.imu.2020.100407","article-title":"Predicted therapeutic targets for COVID-19 disease by inhibiting SARS-CoV-2 and its related receptors","volume":"20","author":"Balmeh","year":"2020","journal-title":"Inform. Med. Unlocked"},{"key":"ref_36","first-page":"E014","article-title":"Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia","volume":"43","author":"Sun","year":"2020","journal-title":"Zhonghua Jie He He Hu Xi Za Zhi"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/femspd\/ftaa036","article-title":"Transcriptome-based drug repositioning for coronavirus disease 2019 (COVID-19)","volume":"78","author":"Jia","year":"2020","journal-title":"Pathog. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Horby, P., Lim, W.S., Emberson, J.R., Mafham, M., Bell, J.L., Linsell, L., Staplin, N., Brightling, C., Ustianowski, A., and Elmahi, E. (2020). Dexamethasone in Hospitalized Patients with Covid-19\u2014Preliminary Report. N. Engl. J. Med.","DOI":"10.1101\/2020.06.22.20137273"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/d41586-020-01824-5","article-title":"Coronavirus breakthrough: Dexamethasone is first drug shown to save lives","volume":"582","author":"Ledford","year":"2020","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Du, F., Liu, B., and Zhang, S. (2020). COVID-19: The role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness. J. Thromb. Thrombolysis.","DOI":"10.1007\/s11239-020-02224-2"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1139\/y02-021","article-title":"ACEH\/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors","volume":"80","author":"Turner","year":"2002","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118205","DOI":"10.1016\/j.lfs.2020.118205","article-title":"Anti-HCV and anti-malaria agent, potential candidates to repurpose for coronavirus infection: Virtual screening, molecular docking, and molecular dynamics simulation study","volume":"258","author":"Hosseini","year":"2020","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7874","DOI":"10.1021\/jm5006463","article-title":"Polypharmacology: Challenges and opportunities in drug discovery","volume":"57","author":"Anighoro","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.2174\/1381612822666160224142812","article-title":"Polypharmacology in Drug Discovery: A Review from Systems Pharmacology Perspective","volume":"22","author":"Zhang","year":"2016","journal-title":"Curr. Pharm. Des."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/11\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:33:46Z","timestamp":1760178826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/11\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,18]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["v12111325"],"URL":"https:\/\/doi.org\/10.3390\/v12111325","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,18]]}}}