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Thyroid hormones, particularly tri-iodothyronine (T3), have been shown to stimulate cardiomyocyte proliferation through activation of the thyroid hormone receptor alpha (TR\u03b1), making this receptor a promising therapeutic target. Here we report a hierarchical and consensus, multi-level virtual screening pipeline integrating Molecular Mechanics (MM), Quantum Mechanics (QM), hybrid QM\/MM calculations, and reactivity analysis based on the Fukui function to identify novel TR\u03b1 agonists. Starting from 412\u00a0million compounds in the ZINC15 database, physicochemical filtering, validated pharmacophore matching, and docking guided by ROC curve optimization yielded 568 candidates, from which eight compounds were selected through chemically guided visual inspection. Binding affinity was evaluated with MD\/MM-PBSA, PM7, and QM\/MM (B3LYP\/6-31G*\/CHARMM36), and complemented by Fukui reactivity mapping to rationalize protein\u2013ligand recognition. Two ligands, including the approved drug Cetraxate, consistently showed favorable interaction energies and reactivity patterns comparable to T3, suggesting agonistic potential. This work provides a rigorous, multi-scale computational framework and identifies two mechanistically supported TR\u03b1 agonist candidates for future experimental validation in cardiac regeneration.<\/jats:p>","DOI":"10.1007\/s10822-026-00787-5","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:32:43Z","timestamp":1774247563000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual screening of compounds for the development of thyroid hormone analogues for potential application in cardiac regeneration"],"prefix":"10.1007","volume":"40","author":[{"given":"Jos\u00e9 de Anchieta","family":"de Oliveira Filho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elton Jos\u00e9 Ferreira","family":"Chaves","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Geraldo","family":"Pascutti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"En\u00e9as Ricardo","family":"de Morais Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"issue":"10159","key":"787_CR1","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1016\/S0140-6736(18)32335-3","volume":"392","author":"HH Kyu","year":"2018","unstructured":"Kyu HH, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N et al (2018) Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017. 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