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Overexpression of ERCC1 correlates with poorer prognosis and response to platinum-based chemotherapy. As a result, there is a pressing need to discover new inhibitors of the ERCC1\u2013XPF complex that can potentiate the efficacy of cisplatin in NSCLC. In this study, we developed a structure-based virtual screening strategy targeting the inhibition of ERCC1 and XPF interaction. Analysis of crystal structures and a library of small molecules known to act against the complex highlighted the pivotal role of Phe293 (ERCC1) in maintaining complex stability. This residue was chosen as the primary binding site for virtual screening. Using an optimized docking protocol, we screened compounds from various databases, ultimately identifying more than one hundred potential inhibitors. Their capability to amplify cisplatin-induced cytotoxicity was assessed in NSCLC H1299 cells, which exhibited the highest ERCC1 expression of all the cell lines tested. Of these, 22 compounds emerged as promising enhancers of cisplatin efficacy. Our results underscore the value of pinpointing crucial molecular characteristics in the pursuit of novel modulators of the ERCC1\u2013XPF interaction, which could be combined with cisplatin to treat NSCLC more effectively.<\/jats:p>","DOI":"10.3390\/ijms25021246","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T08:58:13Z","timestamp":1705654693000},"page":"1246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unveiling Novel ERCC1\u2013XPF Complex Inhibitors: Bridging the Gap from In Silico Exploration to Experimental Design"],"prefix":"10.3390","volume":"25","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"}]},{"given":"Rita B.","family":"Soares","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"}]},{"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":"Catalan Institute of Oncology, 08916 Barcelona, Spain"}]},{"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"}]},{"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":[[2024,1,19]]},"reference":[{"key":"ref_1","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":"Sung","year":"2021","journal-title":"CA Cancer J. 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