Screening the Pathogen Box to Discover and Characterize New Cruzain and <i>Tbr</i>CatL Inhibitors
Thales do Valle Moreira,
Luan Carvalho Martins,
Lucas Abreu Diniz,
Talita Cristina Diniz Bernardes,
Renata Barbosa de Oliveira,
Rafaela Salgado Ferreira
Affiliations
Thales do Valle Moreira
Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Luan Carvalho Martins
Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Lucas Abreu Diniz
Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Talita Cristina Diniz Bernardes
Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Renata Barbosa de Oliveira
Pharmaceutical Products Department, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Rafaela Salgado Ferreira
Molecular Modeling and Drug Design Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, 6627, Antônio Carlos Avenue, Belo Horizonte 31270-901, MG, Brazil
Chagas disease and Human African Trypanosomiasis, caused by Trypanosoma cruzi and T. brucei, respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. 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 ± 0.03 to 27 ± 3 µM. MMV687246 was found to be a mixed inhibitor of cruzain (Ki = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (Ki = 165 ± 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.
