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Overexpression of PPA1 enzyme has been linked to diminished patient survival and was shown to influence tumor cell dynamics, thereby positioning it as a potential therapy target for a variety of cancers including colorectal cancer, diffuse large B\u2010cell lymphoma, and lung adenocarcinoma. Despite this therapeutic promise, there are no known inhibitors of PPA1 as of today. In this study, we searched for potential PPA1 inhibitors using a molecular docking screen of 30\u2009470 compounds with a history of clinical trials and\/or US Food and Drug Administration approval. We specifically targeted the active pocket that coincides with the established catalytic domain. Our screen identified promising hits, which we further subjected to ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering. Subsequent molecular dynamics (MD) analyses were conducted on devazepide, quinotolast, and tarazepide\u2014the three substances that successfully navigated all filters. MD analyses reinforced the stability of the protein\u2010ligand complexes and confirmed ligand binding, as substantiated by our root mean square deviation, radius of gyration and secondary structures of proteins analyses. Furthermore, Molecular Mechanics Poisson\u2010Boltzmann Surface Area calculations post\u2010MD identified devazepide and quinotolast as showing higher binding affinities; being supported by principal component analysis, free energy landscape, and dynamic cross\u2010correlation matrix results. Overall, our study reveals devazepide and quinotolast as potential candidates for PPA1 inhibition which could be considered for repurposing studies that need further experimental validation. These results not only reveal a potential for clinical repurposing for PPA1 inhibition but they also offer valuable insights into the development of future compounds for targeting the crucial PPA1 enzyme.<\/jats:p>","DOI":"10.1002\/jcb.30475","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T17:10:07Z","timestamp":1695316207000},"page":"1646-1663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of PPA1 inhibitor candidates for potential repurposing in cancer medicine"],"prefix":"10.1002","volume":"124","author":[{"given":"Muratcan","family":"Mente\u015f","sequence":"first","affiliation":[{"name":"Department of Genetics and Bioengineering Faculty of Engineering, \u0130zmir University of Economics Bal\u00e7ova \u0130zmir 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