Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening

Autores
Echeverría, Emiliana Beatriz; Velez Rueda, Ana Julia; Cabrera, Maia Diana Eliana; Juritz, Ezequiel; Burghi, Valeria; Fabian, Lucas Emanuel; Davio, Carlos Alberto; Lorenzano Menna, Pablo; Fernandez, Natalia Cristina
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims: G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45–178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging. Key findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.
Fil: Echeverría, Emiliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Velez Rueda, Ana Julia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Juritz, Ezequiel. Universidad Nacional de Quilmes; Argentina. Universidad Andrés Bello; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Burghi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Fabian, Lucas Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina
Fil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Materia
CADD
DBVS
GPCR
GRK2
PPI
RH
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/130707
Acceder
id CONICETDig_8a0f79495bbf783efffc27774c6f377d
oai_identifier_str oai:ri.conicet.gov.ar:11336/130707
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screeningEcheverría, Emiliana BeatrizVelez Rueda, Ana JuliaCabrera, Maia Diana ElianaJuritz, EzequielBurghi, ValeriaFabian, Lucas EmanuelDavio, Carlos AlbertoLorenzano Menna, PabloFernandez, Natalia CristinaCADDDBVSGPCRGRK2PPIRHhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Aims: G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45–178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging. Key findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.Fil: Echeverría, Emiliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Velez Rueda, Ana Julia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; ArgentinaFil: Juritz, Ezequiel. Universidad Nacional de Quilmes; Argentina. Universidad Andrés Bello; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Burghi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Fabian, Lucas Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaPergamon-Elsevier Science Ltd2019-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/130707Echeverría, Emiliana Beatriz; Velez Rueda, Ana Julia; Cabrera, Maia Diana Eliana; Juritz, Ezequiel; Burghi, Valeria; et al.; Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening; Pergamon-Elsevier Science Ltd; Life Sciences; 239; 9-2019; 1-440024-3205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0024320519307994info:eu-repo/semantics/altIdentifier/doi/10.1016/j.lfs.2019.116872info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:29:56Zoai:ri.conicet.gov.ar:11336/130707instacron: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 10:29:56.445CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
title Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
spellingShingle Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
Echeverría, Emiliana Beatriz
CADD
DBVS
GPCR
GRK2
PPI
RH
title_short Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
title_full Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
title_fullStr Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
title_full_unstemmed Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
title_sort Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening
dc.creator.none.fl_str_mv Echeverría, Emiliana Beatriz
Velez Rueda, Ana Julia
Cabrera, Maia Diana Eliana
Juritz, Ezequiel
Burghi, Valeria
Fabian, Lucas Emanuel
Davio, Carlos Alberto
Lorenzano Menna, Pablo
Fernandez, Natalia Cristina
author Echeverría, Emiliana Beatriz
author_facet Echeverría, Emiliana Beatriz
Velez Rueda, Ana Julia
Cabrera, Maia Diana Eliana
Juritz, Ezequiel
Burghi, Valeria
Fabian, Lucas Emanuel
Davio, Carlos Alberto
Lorenzano Menna, Pablo
Fernandez, Natalia Cristina
author_role author
author2 Velez Rueda, Ana Julia
Cabrera, Maia Diana Eliana
Juritz, Ezequiel
Burghi, Valeria
Fabian, Lucas Emanuel
Davio, Carlos Alberto
Lorenzano Menna, Pablo
Fernandez, Natalia Cristina
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CADD
DBVS
GPCR
GRK2
PPI
RH
topic CADD
DBVS
GPCR
GRK2
PPI
RH
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Aims: G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45–178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging. Key findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.
Fil: Echeverría, Emiliana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Velez Rueda, Ana Julia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina
Fil: Juritz, Ezequiel. Universidad Nacional de Quilmes; Argentina. Universidad Andrés Bello; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Burghi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Fabian, Lucas Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina
Fil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnologia. Laboratorio de Farmacologia Molecular.; Argentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
description Aims: G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45–178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging. Key findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.
publishDate 2019
dc.date.none.fl_str_mv 2019-09
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/11336/130707
Echeverría, Emiliana Beatriz; Velez Rueda, Ana Julia; Cabrera, Maia Diana Eliana; Juritz, Ezequiel; Burghi, Valeria; et al.; Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening; Pergamon-Elsevier Science Ltd; Life Sciences; 239; 9-2019; 1-44
0024-3205
CONICET Digital
CONICET
url http://hdl.handle.net/11336/130707
identifier_str_mv Echeverría, Emiliana Beatriz; Velez Rueda, Ana Julia; Cabrera, Maia Diana Eliana; Juritz, Ezequiel; Burghi, Valeria; et al.; Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening; Pergamon-Elsevier Science Ltd; Life Sciences; 239; 9-2019; 1-44
0024-3205
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://linkinghub.elsevier.com/retrieve/pii/S0024320519307994
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.lfs.2019.116872
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
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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