Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach

DOI record: { "DOI": "10.18633/biotecnia.v27.2485", "ISSN": [ "1665-1456", "1665-1456" ], "URL": "http://dx.doi.org/10.18633/biotecnia.v27.2485", "abstract": "<jats:p>Ivermectin has been shown in vitro that reduces SARS-CoV-2 replication in infected cells through interactions with importins α, however, the exact mechanism of action is still unknown. The objective of this study was to analyze binding affinities of ivermectin, SARS-CoV-2 nucleocapsid (N) and ORF6 proteins, to isoforms of human importins α using molecular docking methods. Crystallized structures of importins α from Protein Data Bank (PDB) and AlphaFold Protein Structure Database were used, viral proteins were modeled using AlphaFold 2. Molecular docking simulations were performed between human importin α isoforms, ivermectin, N and ORF6 proteins, employing Broyden-Fletcher-Goldfarb-Shanno, FTDock and pyDockRST algorithms. Data obtained evidenced that viral proteins of SARS-CoV-2 and ivermectin showed favorable binding affinities to ARM2-ARM4 domains (major binding site), sharing binding affinities to the same active residues. These results suggest that ivermectin shares the same active site on the α-importins as the SARS-CoV-2 N and ORF6 proteins, demonstrating a potential molecular target for research in the development of new antiviral drugs against COVID-19.</jats:p>", "author": [ { "ORCID": "https://orcid.org/0000-0001-9309-7056", "affiliation": [], "authenticated-orcid": false, "family": "Gayozo", "given": "Elvio", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-8341-7746", "affiliation": [], "authenticated-orcid": false, "family": "Rojas", "given": "Laura", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4120-4141", "affiliation": [], "authenticated-orcid": false, "family": "Barrios", "given": "Julio", "sequence": "additional" } ], "container-title": "Biotecnia", "container-title-short": "BIOTECNIA", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 3, 18 ] ], "date-time": "2025-03-18T20:53:10Z", "timestamp": 1742331190000 }, "deposited": { "date-parts": [ [ 2025, 3, 18 ] ], "date-time": "2025-03-18T20:53:30Z", "timestamp": 1742331210000 }, "indexed": { "date-parts": [ [ 2025, 3, 19 ] ], "date-time": "2025-03-19T04:33:22Z", "timestamp": 1742358802766, "version": "3.40.1" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2025, 3, 13 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by-nc-sa/4.0", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 3, 13 ] ], "date-time": "2025-03-13T00:00:00Z", "timestamp": 1741824000000 } } ], "link": [ { "URL": "https://www.biotecnia.unison.mx/index.php/biotecnia/article/download/2485/1391", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.biotecnia.unison.mx/index.php/biotecnia/article/download/2485/1392", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.biotecnia.unison.mx/index.php/biotecnia/article/download/2485/1391", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "7961", "original-title": [], "page": "e2485", "prefix": "10.18633", "published": { "date-parts": [ [ 2025, 3, 13 ] ] }, "published-online": { "date-parts": [ [ 2025, 3, 13 ] ] }, "publisher": "Universidad de Sonora", "reference": [ { "DOI": "10.1128/mBio.00065-21", "doi-asserted-by": "crossref", "key": "75797", "unstructured": "Addetia, A., Lieberman, N. 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BMC Microbiology, 21(1), 58. https://doi.org/10.1186/s12866-021-02107-3" }, { "DOI": "10.56152/ffs.v12i2.2219", "doi-asserted-by": "crossref", "key": "75819", "unstructured": "Gayozo, E., Rojas, L. and López, M. 2020. Análisis computacional de la interacción in silico de la Agatisflavona con la región de trimerización de la proteína espícula (S) del SARS-CoV-2. Steviana, 12(2), 70-80. https://doi.org/10.56152/StevianaFacenV12N2A4_2020" }, { "DOI": "10.15446/rev.colomb.biote.v23n2.94466", "doi-asserted-by": "crossref", "key": "75820", "unstructured": "Gayozo, E. and Rojas, L. 2021. Interacción in silico de las moléculas Agathisflavona, Amentoflavona y Punicalina con la Importina α1 humana. Revista Colombiana de Biotecnología, 23(2), 15-24. https://doi.org/10.15446/rev.colomb.biote.v23n2.94466" }, { "DOI": "10.1038/s41586-020-2286-9", "doi-asserted-by": "crossref", "key": "75821", "unstructured": "Gordon, D. E., Jang, G. M., Bouhaddou, M., Xu, J., Obernier, K., White, K. M., O’Meara, M. 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A., Ke, S., Hart, D. J., Zachariae, U. and Cingolani, G. 2015. Molecular Determinants for Nuclear Import of Influenza A PB2 by Importin α Isoforms 3 and 7. Structure, 23(2), 374-384. https://doi.org/10.1016/j.str.2014.11.015" }, { "DOI": "10.1042/BJ20141186", "doi-asserted-by": "crossref", "key": "75850", "unstructured": "Pumroy, R. and Cingolani, G. 2015. Diversification of importin-α isoforms in cellular trafficking and disease states. The Biochemical journal. https://doi.org/10.1042/BJ20141186" }, { "DOI": "10.1002/jmv.20095", "doi-asserted-by": "crossref", "key": "75851", "unstructured": "Qinfen, Z., Jinming, C., Xiaojun, H., Huanying, Z., Jicheng, H., Ling, F., Kunpeng, L. and Jingqiang, Z. 2004. The life cycle of SARS coronavirus in Vero E6 cells. Journal of Medical Virology, 73(3), 332-337. https://doi.org/10.1002/jmv.20095" }, { "DOI": "10.1007/s00210-020-01902-5", "doi-asserted-by": "crossref", "key": "75852", "unstructured": "Rizzo, E. 2020. Ivermectin, antiviral properties and COVID-19: A possible new mechanism of action. Naunyn-Schmiedeberg’s Archives of Pharmacology, 393(7), 1153-1156. https://doi.org/10.1007/s00210-020-01902-5" }, { "DOI": "10.1093/nar/gku316", "doi-asserted-by": "crossref", "key": "75853", "unstructured": "Robert, X. and Gouet, P. 2014. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Research, 42(W1), W320-W324. https://doi.org/10.1093/nar/gku316" }, { "DOI": "10.1128/JVI.79.17.11507-11512.2005", "doi-asserted-by": "crossref", "key": "75854", "unstructured": "Rowland, R. R. R., Chauhan, V., Fang, Y., Pekosz, A., Kerrigan, M. and Burton, M. D. 2005. Intracellular Localization of the Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Protein: Absence of Nucleolar Accumulation during Infection and after Expression as a Recombinant Protein in Vero Cells. 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Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin. Journal of Biomolecular Structure and Dynamics, 40(5), 2217-2226. https://doi.org/10.1080/07391102.2020.1839564" }, { "DOI": "10.1016/j.jare.2020.03.005", "doi-asserted-by": "crossref", "key": "75858", "unstructured": "Shereen, M. A., Khan, S., Kazmi, A., Bashir, N. and Siddique, R. 2020. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. Journal of Advanced Research, 24, 91-98. https://doi.org/10.1016/j.jare.2020.03.005" }, { "DOI": "10.1007/978-1-62703-646-7_6", "doi-asserted-by": "crossref", "key": "75859", "unstructured": "Sievers, F. and Higgins, D. G. 2014. Clustal Omega, Accurate Alignment of Very Large Numbers of Sequences. En D. J. Russell (Ed.), Multiple Sequence Alignment Methods (pp. 105-116). 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