{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:51:50Z","timestamp":1784829110115,"version":"3.55.0"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010747","name":"Consejo Nacional de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["375-2019-FONDECYT"],"award-info":[{"award-number":["375-2019-FONDECYT"]}],"id":[{"id":"10.13039\/501100010747","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universidad de Piura","award":["PI2105"],"award-info":[{"award-number":["PI2105"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) is a type of lung cancer associated with translocation of the EML4 and ALK genes on the short arm of chromosome 2. This leads to the development of an aberrant protein kinase with a deregulated catalytic domain, the cdALK<jats:sup>+<\/jats:sup>. Currently, different ALK inhibitors (iALKs) have been proposed to treat ALK<jats:sup>+<\/jats:sup> NSCLC patients. However, the recent resistance to iALKs stimulates the exploration of new iALKs for NSCLC. Here, we describe an <jats:italic>in silico<\/jats:italic> approach to finding FDA-approved drugs that can be used by pharmacological repositioning as iALK. We used homology modelling to obtain a structural model of cdALK<jats:sup>+<\/jats:sup> protein and then performed molecular docking and molecular dynamics of the complex cdALK<jats:sup>+<\/jats:sup>-iALKs to generate the pharmacophore model. The pharmacophore was used to identify potential iALKs from FDA-approved drugs library by ligand-based virtual screening. Four pharmacophores with different atomistic characteristics were generated, resulting in six drugs that satisfied the proposed atomistic positions and coupled at the ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best interaction energies with 228.29, 165.40 and 133.48 KJoul\/mol respectively. In addition, the special literature proposed these drugs for other types of diseases due to pharmacological repositioning. This study proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover, we identified pharmacophores sites that can be tested with other pharmacological libraries.<\/jats:p>","DOI":"10.1371\/journal.pone.0295966","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T18:28:57Z","timestamp":1707244137000},"page":"e0295966","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitoxantrone and abacavir: An ALK protein-targeted in silico proposal for the treatment of non-small cell lung cancer"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3408-7971","authenticated-orcid":true,"given":"Juan Enrique","family":"Faya Castillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard Junior","family":"Zapata Dongo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Alberto","family":"Wong Chero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefany Fiorella","family":"Infante Varillas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,6]]},"reference":[{"key":"pone.0295966.ref001","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"pone.0295966.ref002","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000487440","article-title":"Heterogeneity in Lung Cancer.","volume":"85","author":"VM de Sousa","year":"2018","journal-title":"Pathobiology"},{"key":"pone.0295966.ref003","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.soc.2016.02.003","article-title":"Classification and Pathology of Lung Cancer.","volume":"25","author":"M. 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ALK Inhib Treat ALK Posit NSCLC.","volume":"8","author":"M Khan","year":"2019","journal-title":"Front Oncol."},{"key":"pone.0295966.ref006","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1182\/blood.V66.4.848.848","article-title":"The expression of the Hodgkin\u2019s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells","volume":"66","author":"H Stein","year":"1985","journal-title":"Blood"},{"key":"pone.0295966.ref007","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.1038\/sj.onc.1204594","article-title":"Translocations involving anaplastic lymphoma kinase (ALK).","volume":"20","author":"J Duyster","year":"2001","journal-title":"Oncogene"},{"key":"pone.0295966.ref008","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/modpathol.2017.181","article-title":"Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer","volume":"31","author":"JN Rosenbaum","year":"2018","journal-title":"Mod Pathol"},{"key":"pone.0295966.ref009","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.lungcan.2021.06.012","article-title":"Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC.","volume":"158","author":"SS Zhang","year":"2021","journal-title":"Lung Cancer"},{"key":"pone.0295966.ref010","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1158\/1078-0432.CCR-14-2791","article-title":"Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: A paradigm for precision cancer medicine","volume":"21","author":"R Katayama","year":"2015","journal-title":"Clin Cancer Res"},{"key":"pone.0295966.ref011","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1007\/s00018-015-2117-6","article-title":"Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs","volume":"73","author":"R Bayliss","year":"2016","journal-title":"Cell Mol Life Sci"},{"key":"pone.0295966.ref012","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2183\/pjab.91.193","article-title":"The EML4-ALK oncogene: targeting an essential growth driver in human cancer","volume":"91","author":"H. 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Doumat","year":"2023","journal-title":"Curr Oncol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295966","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T18:29:37Z","timestamp":1707244177000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295966"}},"subtitle":[],"editor":[{"given":"Chandrabose","family":"Selvaraj","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,2,6]]},"references-count":54,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0295966","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,6]]}}}