New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design

Autores
Barrera Guisasola, Exequiel Ernesto; Andujar, Sebastian Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; Mendez, Luciana; Delpiccolo, Carina Maria Lujan; Masman, Marcelo Fabricio; Rodríguez, Ana M.; Enriz, Ricardo Daniel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.
Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Hubin, Ellen. University of Twente; Países Bajos. Vrije Universiteit Brussel; Bélgica
Fil: Broersen, Kerensa. University of Twente; Países Bajos
Fil: Kraan, Ivonne M.. University of Twente; Países Bajos
Fil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina
Fil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina
Fil: Masman, Marcelo Fabricio. University Of Groningen; Países Bajos
Fil: Rodríguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Materia
Molecular
Modelling
Mimetic
Peptides
Amyloid
Beta-Rpotein
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/7809
Acceder
id CONICETDig_7de10ab18949c9da52f36d264aeb599f
oai_identifier_str oai:ri.conicet.gov.ar:11336/7809
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug designBarrera Guisasola, Exequiel ErnestoAndujar, Sebastian AntonioHubin, EllenBroersen, KerensaKraan, Ivonne M.Mendez, LucianaDelpiccolo, Carina Maria LujanMasman, Marcelo FabricioRodríguez, Ana M.Enriz, Ricardo DanielMolecularModellingMimeticPeptidesAmyloidBeta-Rpoteinhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Hubin, Ellen. University of Twente; Países Bajos. Vrije Universiteit Brussel; BélgicaFil: Broersen, Kerensa. University of Twente; Países BajosFil: Kraan, Ivonne M.. University of Twente; Países BajosFil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; ArgentinaFil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; ArgentinaFil: Masman, Marcelo Fabricio. University Of Groningen; Países BajosFil: Rodríguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaElsevier2015-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/7809Barrera Guisasola, Exequiel Ernesto; Andujar, Sebastian Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; et al.; New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design; Elsevier; European Journal of Medicinal Chemistry; 95; 5-2015; 136-1520009-4374enginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2015.03.042info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0223523415002093info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:49Zoai:ri.conicet.gov.ar:11336/7809instacron: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 09:53:49.549CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
title New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
spellingShingle New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
Barrera Guisasola, Exequiel Ernesto
Molecular
Modelling
Mimetic
Peptides
Amyloid
Beta-Rpotein
title_short New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
title_full New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
title_fullStr New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
title_full_unstemmed New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
title_sort New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
dc.creator.none.fl_str_mv Barrera Guisasola, Exequiel Ernesto
Andujar, Sebastian Antonio
Hubin, Ellen
Broersen, Kerensa
Kraan, Ivonne M.
Mendez, Luciana
Delpiccolo, Carina Maria Lujan
Masman, Marcelo Fabricio
Rodríguez, Ana M.
Enriz, Ricardo Daniel
author Barrera Guisasola, Exequiel Ernesto
author_facet Barrera Guisasola, Exequiel Ernesto
Andujar, Sebastian Antonio
Hubin, Ellen
Broersen, Kerensa
Kraan, Ivonne M.
Mendez, Luciana
Delpiccolo, Carina Maria Lujan
Masman, Marcelo Fabricio
Rodríguez, Ana M.
Enriz, Ricardo Daniel
author_role author
author2 Andujar, Sebastian Antonio
Hubin, Ellen
Broersen, Kerensa
Kraan, Ivonne M.
Mendez, Luciana
Delpiccolo, Carina Maria Lujan
Masman, Marcelo Fabricio
Rodríguez, Ana M.
Enriz, Ricardo Daniel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Molecular
Modelling
Mimetic
Peptides
Amyloid
Beta-Rpotein
topic Molecular
Modelling
Mimetic
Peptides
Amyloid
Beta-Rpotein
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.
Fil: Barrera Guisasola, Exequiel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Hubin, Ellen. University of Twente; Países Bajos. Vrije Universiteit Brussel; Bélgica
Fil: Broersen, Kerensa. University of Twente; Países Bajos
Fil: Kraan, Ivonne M.. University of Twente; Países Bajos
Fil: Mendez, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina
Fil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina
Fil: Masman, Marcelo Fabricio. University Of Groningen; Países Bajos
Fil: Rodríguez, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis; Argentina
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
description A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands.
publishDate 2015
dc.date.none.fl_str_mv 2015-05
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/11336/7809
Barrera Guisasola, Exequiel Ernesto; Andujar, Sebastian Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; et al.; New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design; Elsevier; European Journal of Medicinal Chemistry; 95; 5-2015; 136-152
0009-4374
url http://hdl.handle.net/11336/7809
identifier_str_mv Barrera Guisasola, Exequiel Ernesto; Andujar, Sebastian Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; et al.; New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design; Elsevier; European Journal of Medicinal Chemistry; 95; 5-2015; 136-152
0009-4374
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2015.03.042
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0223523415002093
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
_version_ 1842269249447395328
score 13.13397

Publicaciones similares