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Current therapeutic options are limited by severe adverse effects, toxicity, and drug resistance, highlighting the urgent need for novel treatment strategies. Arginase from <jats:italic>Leishmania<\/jats:italic> spp. (<jats:italic>Lam<\/jats:italic>ARG) has been identified as a promising therapeutic target due to its pivotal role in parasite survival and proliferation. Drug repurposing offers a strategic advantage by accelerating the identification of new therapeutics with established safety profiles, as demonstrated by repurposed agents such as miltefosine, amphotericin B, and paromomycin. This study aimed to identify FDA\u2010approved drugs with inhibitory potential against <jats:italic>Lam<\/jats:italic>ARG, leveraging structure\u2010 and ligand\u2010based computational approaches. A three\u2010dimensional model of <jats:italic>Lam<\/jats:italic>ARG was constructed through comparative modeling, followed by the compilation of known inhibitors from the literature. Molecular docking analyzed their binding interactions, generating pharmacophore hypotheses. These models were validated and applied for virtual screening of FDA\u2010approved compounds from the e\u2010Drug 3D database. Hits identified through pharmacophore\u2010based screening were further evaluated using molecular docking and molecular dynamics simulations to elucidate their binding modes and stability within the catalytic site of <jats:italic>Lam<\/jats:italic>ARG. Our findings indicate that Dabigatran exhibits strong binding affinity and key interactions within the active site of <jats:italic>Lam<\/jats:italic>ARG, suggesting its potential as a viable therapeutic candidate. With strong binding affinity, oral bioavailability, and a well\u2010established safety profile, Dabigatran emerges as a promising repurposed drug against cutaneous leishmaniasis, offering a novel, patient\u2010friendly therapeutic option to overcome treatment limitations and resistance challenges.<\/jats:p>","DOI":"10.1002\/jcb.70060","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T06:00:37Z","timestamp":1755928837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unveiling Novel Arginase Inhibitors for Cutaneous Leishmaniasis Using Drug Repurposing and Virtual Screening Approaches"],"prefix":"10.1002","volume":"126","author":[{"given":"Eduarda Moreira","family":"Barreto","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Modeling &amp; QSAR, Faculty of Pharmacy Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4499-4743","authenticated-orcid":false,"given":"Gabriel Rodrigues Coutinho","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling &amp; 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