Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species
- Autores
- Ochoa, Rodrigo; Ortega Pajares, Amaya; Castello, Florencia Andrea; Serral, Federico; Fernández Do Porto, Darío Augusto; Villa Pulgarin, Janny A.; Varela M., Rubén E.; Muskus, Carlos
- Año de publicación
- 2021
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.
Fil: Ochoa, Rodrigo. Universidad de Antioquia; Colombia
Fil: Ortega Pajares, Amaya. University of Melbourne; Australia
Fil: Castello, Florencia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina
Fil: Serral, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina
Fil: Fernández Do Porto, Darío Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Villa Pulgarin, Janny A.. Coorporación Universitaria Remington; Colombia
Fil: Varela M., Rubén E.. Universidad Santiago de Cali; Colombia
Fil: Muskus, Carlos. Universidad de Antioquia; Colombia - Materia
-
Kinases
Bioinformatics
Drug discovery
Molecular docking
PI3K/AKT pathway - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/171325
Ver los metadatos del registro completo
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Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania SpeciesOchoa, RodrigoOrtega Pajares, AmayaCastello, Florencia AndreaSerral, FedericoFernández Do Porto, Darío AugustoVilla Pulgarin, Janny A.Varela M., Rubén E.Muskus, CarlosKinasesBioinformaticsDrug discoveryMolecular dockingPI3K/AKT pathwayhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.Fil: Ochoa, Rodrigo. Universidad de Antioquia; ColombiaFil: Ortega Pajares, Amaya. University of Melbourne; AustraliaFil: Castello, Florencia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; ArgentinaFil: Serral, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; ArgentinaFil: Fernández Do Porto, Darío Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Villa Pulgarin, Janny A.. Coorporación Universitaria Remington; ColombiaFil: Varela M., Rubén E.. Universidad Santiago de Cali; ColombiaFil: Muskus, Carlos. Universidad de Antioquia; ColombiaMultidisciplinary Digital Publishing Institute2021-07-16info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/171325Ochoa, Rodrigo; Ortega Pajares, Amaya; Castello, Florencia Andrea; Serral, Federico; Fernández Do Porto, Darío Augusto; et al.; Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species; Multidisciplinary Digital Publishing Institute; Biomolecules; 11; 7; 16-7-2021; 1-162218-273XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2218-273X/11/7/1037info:eu-repo/semantics/altIdentifier/doi/10.3390/biom11071037info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:25Zoai:ri.conicet.gov.ar:11336/171325instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:43:25.749CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
title |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
spellingShingle |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species Ochoa, Rodrigo Kinases Bioinformatics Drug discovery Molecular docking PI3K/AKT pathway |
title_short |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
title_full |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
title_fullStr |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
title_full_unstemmed |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
title_sort |
Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species |
dc.creator.none.fl_str_mv |
Ochoa, Rodrigo Ortega Pajares, Amaya Castello, Florencia Andrea Serral, Federico Fernández Do Porto, Darío Augusto Villa Pulgarin, Janny A. Varela M., Rubén E. Muskus, Carlos |
author |
Ochoa, Rodrigo |
author_facet |
Ochoa, Rodrigo Ortega Pajares, Amaya Castello, Florencia Andrea Serral, Federico Fernández Do Porto, Darío Augusto Villa Pulgarin, Janny A. Varela M., Rubén E. Muskus, Carlos |
author_role |
author |
author2 |
Ortega Pajares, Amaya Castello, Florencia Andrea Serral, Federico Fernández Do Porto, Darío Augusto Villa Pulgarin, Janny A. Varela M., Rubén E. Muskus, Carlos |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
Kinases Bioinformatics Drug discovery Molecular docking PI3K/AKT pathway |
topic |
Kinases Bioinformatics Drug discovery Molecular docking PI3K/AKT pathway |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite. Fil: Ochoa, Rodrigo. Universidad de Antioquia; Colombia Fil: Ortega Pajares, Amaya. University of Melbourne; Australia Fil: Castello, Florencia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina Fil: Serral, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina Fil: Fernández Do Porto, Darío Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Villa Pulgarin, Janny A.. Coorporación Universitaria Remington; Colombia Fil: Varela M., Rubén E.. Universidad Santiago de Cali; Colombia Fil: Muskus, Carlos. Universidad de Antioquia; Colombia |
description |
Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases’ participation in protein–protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-07-16 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/171325 Ochoa, Rodrigo; Ortega Pajares, Amaya; Castello, Florencia Andrea; Serral, Federico; Fernández Do Porto, Darío Augusto; et al.; Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species; Multidisciplinary Digital Publishing Institute; Biomolecules; 11; 7; 16-7-2021; 1-16 2218-273X CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/171325 |
identifier_str_mv |
Ochoa, Rodrigo; Ortega Pajares, Amaya; Castello, Florencia Andrea; Serral, Federico; Fernández Do Porto, Darío Augusto; et al.; Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway of Leishmania Species; Multidisciplinary Digital Publishing Institute; Biomolecules; 11; 7; 16-7-2021; 1-16 2218-273X CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2218-273X/11/7/1037 info:eu-repo/semantics/altIdentifier/doi/10.3390/biom11071037 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
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openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.13397 |