Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Abstract
- <jats:p>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.</jats:p>
- Autoren
- Thales do Valle Moreira
- Luan Carvalho Martins
- Lucas Abreu Diniz
- Talita Cristina Diniz Bernardes
- Renata Barbosa de Oliveira
- Rafaela Salgado Ferreira
- DOI
- 10.3390/pathogens12020251
- eISSN
- 2076-0817
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Pathogens
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 251 - 251
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/pathogens12020251
- Datum der Datenerfassung
- 2023
- Titel
- Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors
- Ausgabe der Zeitschrift
- 12
Datenquelle: Crossref
- Andere Metadatenquellen:
-
- Abstract
- Chagas disease and Human African Trypanosomiasis, caused by <i>Trypanosoma cruzi</i> and <i>T. brucei</i>, 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 <i>Tbr</i>CatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC<sub>50</sub> values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC<sub>50</sub> 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 (<i>K<sub>i</sub></i> = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (<i>K<sub>i</sub></i> = 165 ± 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and <i>Tbr</i>CatL are of great interest for further optimization by the medicinal chemistry community.
- Addresses
- 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.
- Autoren
- Thales do Valle Moreira
- Luan Carvalho Martins
- Lucas Abreu Diniz
- Talita Cristina Diniz Bernardes
- Renata Barbosa de Oliveira
- Rafaela Salgado Ferreira
- DOI
- 10.3390/pathogens12020251
- eISSN
- 2076-0817
- Externe Identifier
- PubMed Identifier: 36839523
- PubMed Central ID: PMC9967275
- Funding acknowledgements
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais: APQ-00789-22
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: Finance Code 001
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: A118/2013
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: AUXPE 3379/2013
- National Council for Scientific and Technological Development: 310197/2021-0
- FAPEMIG:
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais: REDE-00140-16
- CAPES/PrInt postdoctoral scholarship: 88887.683330/2022-00
- CNPq, CAPES: Finance Code 001
- Open access
- true
- ISSN
- 2076-0817
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Pathogens (Basel, Switzerland)
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 251
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- Screening the Pathogen Box to Discover and Characterize New Cruzain and <i>Tbr</i>CatL Inhibitors.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 12
Files
https://www.mdpi.com/2076-0817/12/2/251/pdf?version=1677206546 https://europepmc.org/articles/PMC9967275?pdf=render
Datenquelle: Europe PubMed Central
- Abstract
- 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.
- Date of acceptance
- 2023
- Autoren
- Thales do Valle Moreira
- Luan Carvalho Martins
- Lucas Abreu Diniz
- Talita Cristina Diniz Bernardes
- Renata Barbosa de Oliveira
- Rafaela Salgado Ferreira
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/36839523
- DOI
- 10.3390/pathogens12020251
- Externe Identifier
- PubMed Central ID: PMC9967275
- Funding acknowledgements
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: A118/2013
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: AUXPE 3379/2013
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais: APQ-00789-22
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais: REDE-00140-16
- Coordenação de Aperfeicoamento de Pessoal de Nível Superior: Finance Code 001
- National Council for Scientific and Technological Development: 310197/2021-0
- ISSN
- 2076-0817
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Pathogens
- Schlüsselwörter
- Chagas disease
- Pathogen Box
- cruzain
- drug discovery
- screening
- small molecule inhibitors
- Sprache
- eng
- Country
- Switzerland
- PII
- pathogens12020251
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Titel
- Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 12
Datenquelle: PubMed
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