Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening

Protein–protein interactions (PPIs) take place in many cellular processes, including the activation of cellular cascades, such as the MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular-Regulated Kinase) pathway. Deregulation of these pathways leads to the development of diseases, such as cance...

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Autores: Ortiz-González, Carmen, Berta, Casar, Gozalbes, Rafael, Serrano-Candelas, Eva, Crespo, Piero, Carpio, Laureano E.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::da0a5d858f2aa8d84a2a2da6f92e211f
Acceso en línea:http://hdl.handle.net/10261/426624
Access Level:acceso abierto
Palabra clave:ERK1/2
Molecular modelling
ERK dimerization
MAPK/ERK inhibitors
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spelling Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro ScreeningOrtiz-González, CarmenBerta, CasarGozalbes, RafaelSerrano-Candelas, EvaCrespo, PieroCarpio, Laureano E.ERK1/2Molecular modellingERK dimerizationMAPK/ERK inhibitorsProtein–protein interactions (PPIs) take place in many cellular processes, including the activation of cellular cascades, such as the MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular-Regulated Kinase) pathway. Deregulation of these pathways leads to the development of diseases, such as cancer. DEL-22379 is an ERK2 dimerization inhibitor, which presents anti-tumoral effects, without affecting ERK2 phosphorylation. Our aim was to identify new therapeutic molecules targeting ERK2 dimerization, based on DEL-22379 structure. In this study, we implemented a combination of computational and experimental workflow, which includes in silico techniques, such as scaffold hopping and virtual screening to generate a dataset of candidate compounds, a native PAGE (PolyAcrylamide Gel Electrophoresis) electrophoresis to experimentally screen the potential inhibitors, and a detailed molecular docking and chemical profile prediction to understand the potential mechanism of action of the selected compounds. From an initial dataset of 536 compounds, we obtained two hit molecules that exhibited inhibitory effects on ERK2 dimerization: Drug73 and Drug120. A computational analysis of the mechanism of action, unveiled that Drug73 and Drug120 presented an improved docking score, and better drug-like properties when compared to DEL-22379. This study shows that computational studies, in combination with experimental evaluation, can be useful and efficient to find new therapeutic compounds.This publication is part of the grant DIN2024-013557 funded by MICIU/AEI/10.13039/501100011033. P.C. lab is supported by grant RTI2018-096658B-100 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE); a grant from Asociación Española Contra el Cancer (AECC; GCB141423113); CIBERONC (CB16/12/00273) from the Instituto de Salud Carlos III (ISCIII) and by ASPLA S.A “Encintalo en Rosa” grant.Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Asociación Española Contra el CáncerCentro de Investigación Biomédica en Red (España)Instituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/426624reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/DIN2024-013557The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/ijms262311481https://doi.org/10.3390/ijms262311481Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::da0a5d858f2aa8d84a2a2da6f92e211f2026-05-22T06:33:51Z
dc.title.none.fl_str_mv Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
title Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
spellingShingle Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
Ortiz-González, Carmen
ERK1/2
Molecular modelling
ERK dimerization
MAPK/ERK inhibitors
title_short Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
title_full Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
title_fullStr Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
title_full_unstemmed Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
title_sort Identification and Characterization of ERK2 Dimerization Inhibitors by Integrated In Silico and In Vitro Screening
dc.creator.none.fl_str_mv Ortiz-González, Carmen
Berta, Casar
Gozalbes, Rafael
Serrano-Candelas, Eva
Crespo, Piero
Carpio, Laureano E.
author Ortiz-González, Carmen
author_facet Ortiz-González, Carmen
Berta, Casar
Gozalbes, Rafael
Serrano-Candelas, Eva
Crespo, Piero
Carpio, Laureano E.
author_role author
author2 Berta, Casar
Gozalbes, Rafael
Serrano-Candelas, Eva
Crespo, Piero
Carpio, Laureano E.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Asociación Española Contra el Cáncer
Centro de Investigación Biomédica en Red (España)
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ERK1/2
Molecular modelling
ERK dimerization
MAPK/ERK inhibitors
topic ERK1/2
Molecular modelling
ERK dimerization
MAPK/ERK inhibitors
description Protein–protein interactions (PPIs) take place in many cellular processes, including the activation of cellular cascades, such as the MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular-Regulated Kinase) pathway. Deregulation of these pathways leads to the development of diseases, such as cancer. DEL-22379 is an ERK2 dimerization inhibitor, which presents anti-tumoral effects, without affecting ERK2 phosphorylation. Our aim was to identify new therapeutic molecules targeting ERK2 dimerization, based on DEL-22379 structure. In this study, we implemented a combination of computational and experimental workflow, which includes in silico techniques, such as scaffold hopping and virtual screening to generate a dataset of candidate compounds, a native PAGE (PolyAcrylamide Gel Electrophoresis) electrophoresis to experimentally screen the potential inhibitors, and a detailed molecular docking and chemical profile prediction to understand the potential mechanism of action of the selected compounds. From an initial dataset of 536 compounds, we obtained two hit molecules that exhibited inhibitory effects on ERK2 dimerization: Drug73 and Drug120. A computational analysis of the mechanism of action, unveiled that Drug73 and Drug120 presented an improved docking score, and better drug-like properties when compared to DEL-22379. This study shows that computational studies, in combination with experimental evaluation, can be useful and efficient to find new therapeutic compounds.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/426624
url http://hdl.handle.net/10261/426624
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/DIN2024-013557
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.3390/ijms262311481
https://doi.org/10.3390/ijms262311481
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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