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Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and TbrCatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC50 values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC50 values were obtained for six of them (hit rate = 1.5%) and ranged from 0.46 \u00b1 0.03 to 27 \u00b1 3 \u00b5M. MMV687246 was found to be a mixed inhibitor of cruzain (Ki = 57 \u00b1 6 \u00b5M) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (Ki = 165 \u00b1 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and TbrCatL are of great interest for further optimization by the medicinal chemistry community.<\/jats:p>","DOI":"10.3390\/pathogens12020251","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T02:29:23Z","timestamp":1675650563000},"page":"251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors"],"prefix":"10.3390","volume":"12","author":[{"given":"Thales","family":"do Valle Moreira","sequence":"first","affiliation":[{"name":"Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luan Carvalho","family":"Martins","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Abreu","family":"Diniz","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talita Cristina Diniz","family":"Bernardes","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-2567","authenticated-orcid":false,"given":"Renata Barbosa","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Pharmaceutical Products Department, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela Salgado","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Ant\u00f4nio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.2174\/092986710790979953","article-title":"Trypanosomatid Parasites Causing Neglected Diseases","volume":"17","author":"Nussbaum","year":"2010","journal-title":"Curr. 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