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This study utilized computational and experimental approaches, including Density Functional Theory (DFT), molecular docking, pharmacokinetic profiling, and toxicological predictions, to evaluate the potential of these derivatives. The selenium-modified compounds demonstrated improved electronic properties, such as narrower HOMO\u2013LUMO gaps and optimized electronegativity, resulting in enhanced stability and reactivity. Pharmacokinetic analyses revealed favorable absorption, distribution, and blood\u2013brain barrier penetration, while toxicological assessments indicated reduced hepatotoxicity and skin sensitization risks compared to tacrine. Molecular docking and dynamic simulations highlighted strong and stable interactions of the derivatives with critical enzymes, including acetylcholinesterase (AChE) and beta-secretases (BACE1 and BACE2). Compounds 12 and 13, in particular, emerged as the most promising candidates due to their superior stability and binding affinity. These findings underscore the potential of selenium-modified tacrine derivatives as safer and more effective therapeutic agents for Alzheimer\u2019s disease, warranting further experimental validation.<\/jats:p>","DOI":"10.3390\/molecules30122553","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T11:18:40Z","timestamp":1749640720000},"page":"2553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DFT-Based Elucidation and Evaluation of Selenium-Modified Tacrine Derivatives: Theoretical and Physicochemical Insights for Alzheimer\u2019s Disease Therapy"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8377-3604","authenticated-orcid":false,"given":"Roberto Barbosa","family":"Morais","sequence":"first","affiliation":[{"name":"LASOL-CCQFA, Universidade Federal de Pelotas\u2014UFPel, P.O. Box 354-96010-900, Pelotas 96160\u2013000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoela do","family":"Sacramento","sequence":"additional","affiliation":[{"name":"LASOL-CCQFA, Universidade Federal de Pelotas\u2014UFPel, P.O. Box 354-96010-900, Pelotas 96160\u2013000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2194-8670","authenticated-orcid":false,"given":"Cecilia","family":"Scimmi","sequence":"additional","affiliation":[{"name":"Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-6713","authenticated-orcid":false,"given":"Darling de Andrade","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica (Omixlab), Centro de Desenvolvimento Tecnol\u00f3gico (CDTec), Universidade Federal de Pelotas\u2014UFPel, Pelotas 96160\u2013000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederico Schmitt","family":"Kremer","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica (Omixlab), Centro de Desenvolvimento Tecnol\u00f3gico (CDTec), Universidade Federal de Pelotas\u2014UFPel, Pelotas 96160\u2013000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucielli","family":"Savegnago","sequence":"additional","affiliation":[{"name":"Neurobiotechnology Research Group\u2014GPN, Technological Development Center, Federal University of Pelotas\u2014UFPel, Pelotas 96160\u2013000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1074-0294","authenticated-orcid":false,"given":"Diego","family":"Alves","sequence":"additional","affiliation":[{"name":"LASOL-CCQFA, Universidade Federal de Pelotas\u2014UFPel, P.O. 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