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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/171325
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-09-29T09:32:36Zoai: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:34982025-09-29 09:32:36.378CONICET 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/
eu_rights_str_mv 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
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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score 13.070432

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