Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations

Autores
Carlevaro, Carlos Manuel; Martins da Silva, Joao Herminio; Savino, Wilson; Caffarena, Ernesto Raúl
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.
Fil: Carlevaro, Carlos Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Martins da Silva, Joao Herminio. Instituto Oswaldo Cruz; Brasil
Fil: Savino, Wilson. Instituto Oswaldo Cruz; Brasil
Fil: Caffarena, Ernesto Raúl. Instituto Oswaldo Cruz; Brasil
Materia
Integrin
Molecular Dynamics
Binding Mode
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:11336/23640
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculationsCarlevaro, Carlos ManuelMartins da Silva, Joao HerminioSavino, WilsonCaffarena, Ernesto RaúlIntegrinMolecular DynamicsBinding Modehttps://purl.org/becyt/ford/1.3https://purl.org/becyt/ford/1In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.Fil: Carlevaro, Carlos Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Martins da Silva, Joao Herminio. Instituto Oswaldo Cruz; BrasilFil: Savino, Wilson. Instituto Oswaldo Cruz; BrasilFil: Caffarena, Ernesto Raúl. Instituto Oswaldo Cruz; BrasilWorld Scientific2012-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/23640Carlevaro, Carlos Manuel; Martins da Silva, Joao Herminio ; Savino, Wilson; Caffarena, Ernesto Raúl; Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations; World Scientific; Journal Of Theoretical And Computational Chemistry; 12; 2; 12-2012; 1-16; 12501080219-6336CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1142/S0219633612501088info:eu-repo/semantics/altIdentifier/url/http://www.worldscientific.com/doi/abs/10.1142/S0219633612501088info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-17T11:19:50Zoai:ri.conicet.gov.ar:11336/23640instacron: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:34982025-09-17 11:19:50.296CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
title Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
spellingShingle Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
Carlevaro, Carlos Manuel
Integrin
Molecular Dynamics
Binding Mode
title_short Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
title_full Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
title_fullStr Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
title_full_unstemmed Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
title_sort Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations
dc.creator.none.fl_str_mv Carlevaro, Carlos Manuel
Martins da Silva, Joao Herminio
Savino, Wilson
Caffarena, Ernesto Raúl
author Carlevaro, Carlos Manuel
author_facet Carlevaro, Carlos Manuel
Martins da Silva, Joao Herminio
Savino, Wilson
Caffarena, Ernesto Raúl
author_role author
author2 Martins da Silva, Joao Herminio
Savino, Wilson
Caffarena, Ernesto Raúl
author2_role author
author
author
dc.subject.none.fl_str_mv Integrin
Molecular Dynamics
Binding Mode
topic Integrin
Molecular Dynamics
Binding Mode
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.3
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.
Fil: Carlevaro, Carlos Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
Fil: Martins da Silva, Joao Herminio. Instituto Oswaldo Cruz; Brasil
Fil: Savino, Wilson. Instituto Oswaldo Cruz; Brasil
Fil: Caffarena, Ernesto Raúl. Instituto Oswaldo Cruz; Brasil
description In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell tra±cking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active 41 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the 41 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding G values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the 41 binding site were carried out to elucidate the binding energy pro¯le and identify the most signi¯cant residues. Our results indicate that MK-0617 ¯ts within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.
publishDate 2012
dc.date.none.fl_str_mv 2012-12
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/11336/23640
Carlevaro, Carlos Manuel; Martins da Silva, Joao Herminio ; Savino, Wilson; Caffarena, Ernesto Raúl; Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations; World Scientific; Journal Of Theoretical And Computational Chemistry; 12; 2; 12-2012; 1-16; 1250108
0219-6336
CONICET Digital
CONICET
url http://hdl.handle.net/11336/23640
identifier_str_mv Carlevaro, Carlos Manuel; Martins da Silva, Joao Herminio ; Savino, Wilson; Caffarena, Ernesto Raúl; Plausible binding mode of the active α4β1 antagonist, MK-0617, determined by docking and free energy calculations; World Scientific; Journal Of Theoretical And Computational Chemistry; 12; 2; 12-2012; 1-16; 1250108
0219-6336
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1142/S0219633612501088
info:eu-repo/semantics/altIdentifier/url/http://www.worldscientific.com/doi/abs/10.1142/S0219633612501088
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
dc.publisher.none.fl_str_mv World Scientific
publisher.none.fl_str_mv World Scientific
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_ 1843606542936440832
score 13.001348

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