Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Autores
Tosso, Rodrigo David; Andújar, Sebastián Antonio; Gutierrez, Lucas Joel; Angelina, Emilio Luis; Rodriguez, Ricaurte; Nogueras, Manuel; Baldoni, Hector Armando; Suvire, Fernando Daniel; Cobos, Justo; Enriz, Ricardo Daniel
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.
Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; Argentina
Fil: Andújar, Sebastián Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional del Nordeste. Facultad de Cs.exactas Naturales y Agrimensura. Departamento de Quimica. Laboratorio de Estructura Molecular y Propiedades; Argentina
Fil: Rodriguez, Ricaurte. Universidad Nacional de Colombia. Departamento de Química; Colombia
Fil: Nogueras, Manuel. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; España
Fil: Baldoni, Hector Armando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; Argentina
Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Cobos, Justo. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; España
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Materia
Dihydrofolate Reductase
Molecular Modelling
Non Classic Inhibitors
Qtaim
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:11336/4381
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/4381
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental CorroborationTosso, Rodrigo DavidAndújar, Sebastián AntonioGutierrez, Lucas JoelAngelina, Emilio LuisRodriguez, RicaurteNogueras, ManuelBaldoni, Hector ArmandoSuvire, Fernando DanielCobos, JustoEnriz, Ricardo DanielDihydrofolate ReductaseMolecular ModellingNon Classic InhibitorsQtaimhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; ArgentinaFil: Andújar, Sebastián Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional del Nordeste. Facultad de Cs.exactas Naturales y Agrimensura. Departamento de Quimica. Laboratorio de Estructura Molecular y Propiedades; ArgentinaFil: Rodriguez, Ricaurte. Universidad Nacional de Colombia. Departamento de Química; ColombiaFil: Nogueras, Manuel. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; EspañaFil: Baldoni, Hector Armando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; ArgentinaFil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Cobos, Justo. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; EspañaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaAmerican Chemical Society2013-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4381Tosso, Rodrigo David; Andújar, Sebastián Antonio; Gutierrez, Lucas Joel; Angelina, Emilio Luis; Rodriguez, Ricaurte; et al.; Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration; American Chemical Society; Journal of Chemical Information and Modeling; 53; 8; 6-2013; 2018-20321549-9596enginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/ci400178hinfo:eu-repo/semantics/altIdentifier/doi/DOI:10.1021/ci400178hinfo:eu-repo/semantics/altIdentifier/issn/1549-9596info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:14:23Zoai:ri.conicet.gov.ar:11336/4381instacron: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 10:14:23.92CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
title Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
spellingShingle Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
Tosso, Rodrigo David
Dihydrofolate Reductase
Molecular Modelling
Non Classic Inhibitors
Qtaim
title_short Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
title_full Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
title_fullStr Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
title_full_unstemmed Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
title_sort Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration
dc.creator.none.fl_str_mv Tosso, Rodrigo David
Andújar, Sebastián Antonio
Gutierrez, Lucas Joel
Angelina, Emilio Luis
Rodriguez, Ricaurte
Nogueras, Manuel
Baldoni, Hector Armando
Suvire, Fernando Daniel
Cobos, Justo
Enriz, Ricardo Daniel
author Tosso, Rodrigo David
author_facet Tosso, Rodrigo David
Andújar, Sebastián Antonio
Gutierrez, Lucas Joel
Angelina, Emilio Luis
Rodriguez, Ricaurte
Nogueras, Manuel
Baldoni, Hector Armando
Suvire, Fernando Daniel
Cobos, Justo
Enriz, Ricardo Daniel
author_role author
author2 Andújar, Sebastián Antonio
Gutierrez, Lucas Joel
Angelina, Emilio Luis
Rodriguez, Ricaurte
Nogueras, Manuel
Baldoni, Hector Armando
Suvire, Fernando Daniel
Cobos, Justo
Enriz, Ricardo Daniel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dihydrofolate Reductase
Molecular Modelling
Non Classic Inhibitors
Qtaim
topic Dihydrofolate Reductase
Molecular Modelling
Non Classic Inhibitors
Qtaim
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.
Fil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; Argentina
Fil: Andújar, Sebastián Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional del Nordeste. Facultad de Cs.exactas Naturales y Agrimensura. Departamento de Quimica. Laboratorio de Estructura Molecular y Propiedades; Argentina
Fil: Rodriguez, Ricaurte. Universidad Nacional de Colombia. Departamento de Química; Colombia
Fil: Nogueras, Manuel. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; España
Fil: Baldoni, Hector Armando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica Analitica; Argentina
Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Cobos, Justo. Universidad de Jaén. Departamento de Química Inorgánica y Orgánica; España
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigación Biológica de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
description A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.
publishDate 2013
dc.date.none.fl_str_mv 2013-06
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/11336/4381
Tosso, Rodrigo David; Andújar, Sebastián Antonio; Gutierrez, Lucas Joel; Angelina, Emilio Luis; Rodriguez, Ricaurte; et al.; Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration; American Chemical Society; Journal of Chemical Information and Modeling; 53; 8; 6-2013; 2018-2032
1549-9596
url http://hdl.handle.net/11336/4381
identifier_str_mv Tosso, Rodrigo David; Andújar, Sebastián Antonio; Gutierrez, Lucas Joel; Angelina, Emilio Luis; Rodriguez, Ricaurte; et al.; Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration; American Chemical Society; Journal of Chemical Information and Modeling; 53; 8; 6-2013; 2018-2032
1549-9596
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/ci400178h
info:eu-repo/semantics/altIdentifier/doi/DOI:10.1021/ci400178h
info:eu-repo/semantics/altIdentifier/issn/1549-9596
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
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application/pdf
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application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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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