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therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 \u00c5. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 \u00c5, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.<\/jats:p>","DOI":"10.3390\/biom14070755","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T05:11:39Z","timestamp":1719465099000},"page":"755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5569-0868","authenticated-orcid":false,"given":"Yuri Alves","family":"de Oliveira S\u00f3","sequence":"first","affiliation":[{"name":"Institute of Physics, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1019-9642","authenticated-orcid":false,"given":"Katyanna Sales","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal 59078-570, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3823-7436","authenticated-orcid":false,"given":"Ricardo","family":"Gargano","sequence":"additional","affiliation":[{"name":"Institute of Physics, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7100-7304","authenticated-orcid":false,"given":"Fabio L. L.","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, College of Technology, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4115-4829","authenticated-orcid":false,"given":"Janeusa Trindade","family":"Souto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59064-741, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4528-9878","authenticated-orcid":false,"given":"Umberto L.","family":"Fulco","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal 59078-570, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9058-510X","authenticated-orcid":false,"given":"Marcelo Lopes","family":"Pereira Junior","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, College of Technology, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7468-2946","authenticated-orcid":false,"given":"Luiz Ant\u00f4nio Ribeiro","family":"Junior","sequence":"additional","affiliation":[{"name":"Institute of Physics, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"},{"name":"Computational Materials Laboratory, University of Bras\u00edlia, LCCMat, Bras\u00edlia 70919-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1111\/febs.15375","article-title":"A Guide to COVID-19: A global pandemic caused by the novel coronavirus SARS-CoV-2","volume":"287","author":"Atzrodt","year":"2020","journal-title":"FEBS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109819","DOI":"10.1016\/j.envres.2020.109819","article-title":"Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy","volume":"188","author":"Jayaweera","year":"2020","journal-title":"Environ. 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