{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T04:08:30Z","timestamp":1750910910562,"version":"3.41.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah Bint Abdulrahman University","doi-asserted-by":"publisher","award":["PNURSP2025R513"],"award-info":[{"award-number":["PNURSP2025R513"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>The global pandemic, due to the emergence of COVID-19, has created a public health crisis. It has a huge morbidity rate that was never comprehended in the recent decades. Despite numerous efforts, potent antiviral drugs are lacking. Repurposing of drugs presents a low-cost and rapid solution for finding new drugs by exploiting known drugs. In this study, we employed an integrated <jats:italic>In-Silico<\/jats:italic> approach using molecular docking and machine learning regression models to explore the potential inhibitors against key proteins of SARS-CoV-2. A library of 5903 drugs from the ZINC database was retrieved and screened against three crucial viral targets: <jats:italic>Spike<\/jats:italic> glycoprotein <jats:italic>(7LM9)<\/jats:italic>, <jats:italic>main protease 3CLpro (7JSU)<\/jats:italic>, and <jats:italic>Nucleocapsid protein (7DE1).<\/jats:italic> Binding affinities were predicted by using molecular docking, and subsequent predictive regression models, Decision Tree Regression (DTR), Gradient Boosting, XGBoost, Extra Trees, KNNR, and MLP, were constructed employing MACCS molecular fingerprints. Among them, the DTR model had better predictive performance, as indicated by the highest R\u00b2 and lowest RMSE. The highest ranked compounds possessed good binding affinities (\u221212.6 to \u221219.7 kcal\/mol) and favorable pharmacokinetics. Importantly, five novel candidate compounds, namely ZINC003873365, ZINC085432544, ZINC008214470, ZINC085536956, and ZINC261494640, had multi-target potential and optimal binding interaction. This computational analysis yields useful information for lead prioritization and sets the stage for additional <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> confirmation of these drug candidates to combat COVID-19.<\/jats:p>","DOI":"10.1371\/journal.pone.0325707","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T18:22:27Z","timestamp":1750875747000},"page":"e0325707","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["In-silico study of approved drugs as potential inhibitors against 3CLpro and other viral proteins of CoVID-19"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2380-8654","authenticated-orcid":true,"given":"Imra","family":"Aqeel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul","family":"Majid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tahani Jaser","family":"Alahmadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-0062","authenticated-orcid":true,"given":"Areej","family":"Althubaity","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"pone.0325707.ref001","doi-asserted-by":"crossref","first-page":"117652","DOI":"10.1016\/j.lfs.2020.117652","article-title":"In silico studies on therapeutic agents for COVID-19: Drug repurposing approach","volume":"252","author":"B Shah","year":"2020","journal-title":"Life Sci"},{"issue":"9","key":"pone.0325707.ref002","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/S1473-3099(22)00320-6","article-title":"Global impact of the first year of COVID-19 vaccination: a mathematical modelling study","volume":"22","author":"OJ Watson","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"pone.0325707.ref003","article-title":"COVID- vaccine and booster hesitation around the world: A literature review","author":"A Shah","year":"2023","journal-title":"Journal of Global Health"},{"key":"pone.0325707.ref004","doi-asserted-by":"crossref","first-page":"108163","DOI":"10.1016\/j.compbiomed.2024.108163","article-title":"The Discovery of inhibitors of the SARS-CoV-2 S protein through computational drug repurposing","volume":"171","author":"AI Avil\u00e9s-Al\u00eda","year":"2024","journal-title":"Comput Biol Med"},{"key":"pone.0325707.ref005","doi-asserted-by":"crossref","unstructured":"Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. 2020;5883.","DOI":"10.1126\/scitranslmed.abb5883"},{"issue":"4","key":"pone.0325707.ref006","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1053\/j.ajkd.2022.01.001","article-title":"Special Considerations for Paxlovid Treatment Among Transplant Recipients With SARS-CoV-2 Infection","volume":"79","author":"S Fishbane","year":"2022","journal-title":"Am J Kidney Dis"},{"key":"pone.0325707.ref007","doi-asserted-by":"crossref","first-page":"105813","DOI":"10.1016\/j.antiviral.2024.105813","article-title":"Drug repurposing platform for deciphering the druggable SARS-CoV-2 interactome","volume":"223","author":"MS Bogacheva","year":"2024","journal-title":"Antiviral Res"},{"issue":"6","key":"pone.0325707.ref008","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1177\/0897190021997399","article-title":"The Rise and Fall of Hydroxychloroquine and Chloroquine in COVID-19","volume":"35","author":"R Aljadeed","year":"2022","journal-title":"J Pharm Pract"},{"key":"pone.0325707.ref009","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ymeth.2023.12.001","article-title":"Using TransR to enhance drug repurposing knowledge graph for COVID-19 and its complications","volume":"221","author":"H Zhao","year":"2024","journal-title":"Methods"},{"key":"pone.0325707.ref010","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.3390\/ph15111333","article-title":"Hybrid approach to identifying druglikeness leading compounds against COVID-19 3CL protease","volume":"15","author":"I Aqeel","year":"2022","journal-title":"Pharmaceuticals"},{"issue":"8","key":"pone.0325707.ref011","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1021\/acs.jcim.1c00384","article-title":"Comprehensive Consensus Analysis of SARS-CoV-2 Drug Repurposing Campaigns","volume":"61","author":"H Mslati","year":"2021","journal-title":"J Chem Inf Model"},{"issue":"10223","key":"pone.0325707.ref012","doi-asserted-by":"crossref","DOI":"10.1016\/S0140-6736(20)30304-4","article-title":"Baricitinib as potential treatment for 2019-nCoV acute respiratory disease","volume":"395","author":"P Richardson","year":"2020","journal-title":"Lancet"},{"issue":"9","key":"pone.0325707.ref013","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa2031994","article-title":"Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19","volume":"384","author":"AC Kalil","year":"2021","journal-title":"N Engl J Med"},{"key":"pone.0325707.ref014","doi-asserted-by":"crossref","first-page":"685","DOI":"10.2147\/DDDT.S354841","article-title":"A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval","volume":"16","author":"NA Ashour","year":"2022","journal-title":"Drug Des Devel Ther"},{"key":"pone.0325707.ref015","doi-asserted-by":"crossref","first-page":"1292280","DOI":"10.3389\/fgene.2024.1292280","article-title":"Identification of potential therapeutic targets for COVID-19 through a structural-based similarity approach between SARS-CoV-2 and its human host proteins","volume":"15","author":"A Tasneem","year":"2024","journal-title":"Front Genet"},{"issue":"2","key":"pone.0325707.ref016","doi-asserted-by":"crossref","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":"M Hoffmann","year":"2020","journal-title":"Cell"},{"key":"pone.0325707.ref017","doi-asserted-by":"crossref","unstructured":"Haid S, Matthaei A, Winkler M, Sake SM, Gunesch AP, Milke V, et al. Repurposing screen identifies novel candidates for broadspectrum coronavirus antivirals and druggable host targets. 2024.","DOI":"10.1128\/aac.01210-23"},{"key":"pone.0325707.ref018","doi-asserted-by":"crossref","unstructured":"Liu Y, Luo Z. Repurposing anticancer drugs targeting the MAPK\/ERK signaling pathway for the treatment of respiratory virus infections. 2024.","DOI":"10.3390\/ijms25136946"},{"key":"pone.0325707.ref019","doi-asserted-by":"crossref","first-page":"1282859","DOI":"10.3389\/fimmu.2023.1282859","article-title":"Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches","volume":"14","author":"A Niarakis","year":"2024","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0325707.ref020","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1038\/s41598-024-55013-9","article-title":"Network analysis-guided drug repurposing strategies targeting LPAR receptor in the interplay of COVID, Alzheimer\u2019s, and diabetes","volume":"14","author":"DS Malar","year":"2024","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0325707.ref021","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3855\/jidc.18189","article-title":"Drug repurposing: identification of SARS-CoV-2 potential inhibitors by virtual screening and pharmacokinetics strategies","volume":"18","author":"Z Rashid","year":"2024","journal-title":"J Infect Dev Ctries"},{"issue":"1","key":"pone.0325707.ref022","doi-asserted-by":"crossref","first-page":"14208","DOI":"10.1038\/s41598-024-61541-1","article-title":"Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics","volume":"14","author":"VP Waman","year":"2024","journal-title":"Sci Rep"},{"key":"pone.0325707.ref023","doi-asserted-by":"crossref","first-page":"148553","DOI":"10.1016\/j.gene.2024.148553","article-title":"Repurposing of antimycobacterium drugs for COVID-19 treatment by targeting SARS CoV-2 main protease: An in-silico perspective","volume":"922","author":"A Chakraborty","year":"2024","journal-title":"Gene"},{"key":"pone.0325707.ref024","doi-asserted-by":"crossref","unstructured":"Bairagya HR, Gupta S, Pal S. Identification of antibiotic drugs against SARS-CoV2 Mpro: a computational approach for drug repurposing. 3:70\u201390.","DOI":"10.61797\/ijbic.v3i1.283"},{"key":"pone.0325707.ref025","doi-asserted-by":"crossref","unstructured":"Ibrahim NA, Gouda AM. Development of a multi-target pharmacophore-based virtual screening against COVID-19. 2024;2.","DOI":"10.62846\/3006-5909.1005"},{"key":"pone.0325707.ref026","doi-asserted-by":"crossref","unstructured":"Ibrahim AA. 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One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325707","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T18:22:38Z","timestamp":1750875758000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0325707"}},"subtitle":[],"editor":[{"given":"Ahmed A.","family":"Al-Karmalawy","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0325707","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]}}}