Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study

Autores
Jara, Gabriel Ernesto; Vera, Domingo Mariano Adolfo; Pierini, Adriana Beatriz
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain
Fil: Jara, Gabriel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Fil: Vera, Domingo Mariano Adolfo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pierini, Adriana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Materia
Mdr
P-Glycoprotein
Abc Transporters
Molecular Docking
Molecular Dynamics
Free Energies of Binding
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:11336/25479
Acceder
id CONICETDig_7bb221cb7bffdf0d942980ee74aed397
oai_identifier_str oai:ri.conicet.gov.ar:11336/25479
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational studyJara, Gabriel ErnestoVera, Domingo Mariano AdolfoPierini, Adriana BeatrizMdrP-GlycoproteinAbc TransportersMolecular DockingMolecular DynamicsFree Energies of Bindinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domainFil: Jara, Gabriel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Vera, Domingo Mariano Adolfo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pierini, Adriana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaElsevier Science Inc2013-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/25479Jara, Gabriel Ernesto; Vera, Domingo Mariano Adolfo; Pierini, Adriana Beatriz; Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study; Elsevier Science Inc; Journal Of Molecular Graphics & Modelling.; 46; 9-2013; 10-211093-3263CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.jmgm.2013.09.001info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S1093326313001563info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:36:44Zoai:ri.conicet.gov.ar:11336/25479instacron: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:34982025-10-22 11:36:44.713CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
title Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
spellingShingle Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
Jara, Gabriel Ernesto
Mdr
P-Glycoprotein
Abc Transporters
Molecular Docking
Molecular Dynamics
Free Energies of Binding
title_short Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
title_full Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
title_fullStr Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
title_full_unstemmed Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
title_sort Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
dc.creator.none.fl_str_mv Jara, Gabriel Ernesto
Vera, Domingo Mariano Adolfo
Pierini, Adriana Beatriz
author Jara, Gabriel Ernesto
author_facet Jara, Gabriel Ernesto
Vera, Domingo Mariano Adolfo
Pierini, Adriana Beatriz
author_role author
author2 Vera, Domingo Mariano Adolfo
Pierini, Adriana Beatriz
author2_role author
author
dc.subject.none.fl_str_mv Mdr
P-Glycoprotein
Abc Transporters
Molecular Docking
Molecular Dynamics
Free Energies of Binding
topic Mdr
P-Glycoprotein
Abc Transporters
Molecular Docking
Molecular Dynamics
Free Energies of Binding
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain
Fil: Jara, Gabriel Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Fil: Vera, Domingo Mariano Adolfo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pierini, Adriana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
description The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain
publishDate 2013
dc.date.none.fl_str_mv 2013-09
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/11336/25479
Jara, Gabriel Ernesto; Vera, Domingo Mariano Adolfo; Pierini, Adriana Beatriz; Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study; Elsevier Science Inc; Journal Of Molecular Graphics & Modelling.; 46; 9-2013; 10-21
1093-3263
CONICET Digital
CONICET
url http://hdl.handle.net/11336/25479
identifier_str_mv Jara, Gabriel Ernesto; Vera, Domingo Mariano Adolfo; Pierini, Adriana Beatriz; Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study; Elsevier Science Inc; Journal Of Molecular Graphics & Modelling.; 46; 9-2013; 10-21
1093-3263
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jmgm.2013.09.001
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S1093326313001563
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
dc.publisher.none.fl_str_mv Elsevier Science Inc
publisher.none.fl_str_mv Elsevier Science Inc
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 12.982451

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