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During the COVID\u201019 pandemic, hundreds of antivirals were developed, many of which remain unexplored for other diseases. Concurrently, machine learning (ML) has become a valuable tool in early drug discovery for screening the most promising compounds for a target. In this work, an ExtraTrees ML model is developed to predict inhibitory activity against cruzain, the main cysteine protease of\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    , the causative agent of Chagas disease. The model is used to screen a proprietary library of peptidomimetic compounds originally designed to target SARS\u2010CoV\u20102 M\n                    <jats:sup>pro<\/jats:sup>\n                    and human cathepsin L. High\u2010affinity cruzain inhibitors are identified, some containing P1 moieties not previously reported in cruzain inhibitors, expanding the known chemical space for this target. Selected hits are validated using isothermal titration calorimetry and some compounds display more favorable enthalpic and entropic contributions to binding than similar peptidomimetic nitrile\u2010based inhibitors. Notably, this is achieved without highly lipophilic R\u2010groups, preserving drug\u2010like properties. This work also highlights how compound libraries derived from global health efforts can be effectively repurposed for neglected tropical diseases with ML models.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500630","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T18:59:53Z","timestamp":1769885993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Machine Learning\u2010Guided Repositioning of a SARS\u2010CoV\u20102\u2010Targeting Molecular Series as Cruzain Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4466-2682","authenticated-orcid":false,"given":"Rafael F.","family":"Lameiro","sequence":"first","affiliation":[{"name":"Medicinal and Biological Chemistry Group S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo  Avenida Trabalhador Sancarlense, 400 S\u00e3o Carlos SP 13566\u2013590 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