{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T03:45:21Z","timestamp":1773114321137,"version":"3.50.1"},"reference-count":65,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["2020.04602.BD"],"award-info":[{"award-number":["2020.04602.BD"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["LISBOA-01-0246-FEDER-000017"],"award-info":[{"award-number":["LISBOA-01-0246-FEDER-000017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["EXPL\/QUI-OUT\/1288\/2021"],"award-info":[{"award-number":["EXPL\/QUI-OUT\/1288\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>NSCLC is marked by low survival and resistance to platinum-based chemotherapy. The XPG endonuclease has emerged as a promising biomarker for predicting the prognosis of cisplatin-treated patients and its downregulation having been reported to increase cisplatin efficacy. This study presents an integrated strategy for identifying small molecule inhibitors of XPG to improve cisplatin therapy in NSCLC. A structure-based virtual screening approach was adopted, including a structural and physicochemical analysis of the protein, and a library of small molecules with reported inhibitory activities was retrieved. This analysis identified Lys84 as a crucial residue for XPG activity by targeting its interaction with DNA. After molecular docking and virtual screening calculations, 61 small molecules were selected as potential XPG inhibitors, acquired from the ChemBridge database and then validated in H1299 cells, a NSCLC cell line exhibiting the highest ERCC5 expression. The MTS assay was performed as a first screening approach to determine whether these potential inhibitors could enhance cisplatin-induced cytotoxicity. Overall, among the eight compounds identified as the most promising, three of them revealed to significantly increase the impact of cisplatin. The inherent cytotoxicity of these compounds was further investigated in a non-tumoral lung cell line (BEAS-2B cells), which resulted in the identification of two non-cytotoxic candidates to be used in combination with cisplatin in order to improve its efficacy in NSCLC therapy.<\/jats:p>","DOI":"10.3390\/cancers16183174","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T10:56:57Z","timestamp":1726484217000},"page":"3174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel DNA Repair Inhibitors Targeting XPG to Enhance Cisplatin Therapy in Non-Small Cell Lung Cancer: Insights from In Silico and Cell-Based Studies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5371-0178","authenticated-orcid":false,"given":"Rita","family":"Manguinhas","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9537-9452","authenticated-orcid":false,"given":"Patr\u00edcia A.","family":"Serra","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"},{"name":"Lung Unit, Champalimaud Clinical Centre (CCC), Champalimaud Foundation, 1400-038 Lisboa, Portugal"},{"name":"Egas Moniz Interdisciplinary Research Center, Instituto Universit\u00e1rio Egas Moniz, 2829-511 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6567-8379","authenticated-orcid":false,"given":"Nuno","family":"Gil","sequence":"additional","affiliation":[{"name":"Lung Unit, Champalimaud Clinical Centre (CCC), Champalimaud Foundation, 1400-038 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0817-3400","authenticated-orcid":false,"given":"Rafael","family":"Rosell","sequence":"additional","affiliation":[{"name":"Dr. Rosell Oncology Institute, 08028 Barcelona, Spain"},{"name":"Institute Germans Trias i Pujol, 08916 Badalona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6114-6829","authenticated-orcid":false,"given":"Nuno G.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/em.22087","article-title":"Mechanisms of DNA damage, repair and mutagenesis Nimrat","volume":"58","author":"Chatterjee","year":"2017","journal-title":"Environ. 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