Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study

Autores
Vega Hissi, Esteban Gabriel; Tosso, Rodrigo David; Enriz, Ricardo Daniel; Gutierrez, Lucas Joel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.
Fil: Vega Hissi, Esteban Gabriel. 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. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas 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. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Gutierrez, Lucas Joel. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Alzheimer
Qtaim
Inhibitor
Modeling
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:11336/14560
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/14560
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM StudyVega Hissi, Esteban GabrielTosso, Rodrigo DavidEnriz, Ricardo DanielGutierrez, Lucas JoelAlzheimerQtaimInhibitorModelinghttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.Fil: Vega Hissi, Esteban Gabriel. 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. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas 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; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Gutierrez, Lucas Joel. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaWiley2015-03info: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/11336/14560Vega Hissi, Esteban Gabriel; Tosso, Rodrigo David; Enriz, Ricardo Daniel; Gutierrez, Lucas Joel; Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study; Wiley; International Journal of Quantum Chemistry; 115; 6; 3-2015; 389-3970020-76081097-461Xenginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/qua.24854/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/qua.24854info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:49:44Zoai:ri.conicet.gov.ar:11336/14560instacron: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 09:49:44.716CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
title Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
spellingShingle Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
Vega Hissi, Esteban Gabriel
Alzheimer
Qtaim
Inhibitor
Modeling
title_short Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
title_full Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
title_fullStr Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
title_full_unstemmed Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
title_sort Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study
dc.creator.none.fl_str_mv Vega Hissi, Esteban Gabriel
Tosso, Rodrigo David
Enriz, Ricardo Daniel
Gutierrez, Lucas Joel
author Vega Hissi, Esteban Gabriel
author_facet Vega Hissi, Esteban Gabriel
Tosso, Rodrigo David
Enriz, Ricardo Daniel
Gutierrez, Lucas Joel
author_role author
author2 Tosso, Rodrigo David
Enriz, Ricardo Daniel
Gutierrez, Lucas Joel
author2_role author
author
author
dc.subject.none.fl_str_mv Alzheimer
Qtaim
Inhibitor
Modeling
topic Alzheimer
Qtaim
Inhibitor
Modeling
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.
Fil: Vega Hissi, Esteban Gabriel. 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. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas 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. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina
Fil: Gutierrez, Lucas Joel. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.
publishDate 2015
dc.date.none.fl_str_mv 2015-03
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/11336/14560
Vega Hissi, Esteban Gabriel; Tosso, Rodrigo David; Enriz, Ricardo Daniel; Gutierrez, Lucas Joel; Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study; Wiley; International Journal of Quantum Chemistry; 115; 6; 3-2015; 389-397
0020-7608
1097-461X
url http://hdl.handle.net/11336/14560
identifier_str_mv Vega Hissi, Esteban Gabriel; Tosso, Rodrigo David; Enriz, Ricardo Daniel; Gutierrez, Lucas Joel; Molecular Insight into the Interaction Mechanisms of Amino-2H-Imidazole Derivatives With BACE1 Protease: A QM/MM and QTAIM Study; Wiley; International Journal of Quantum Chemistry; 115; 6; 3-2015; 389-397
0020-7608
1097-461X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/qua.24854/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/qua.24854
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 Wiley
publisher.none.fl_str_mv Wiley
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_ 1842268991639257088
score 13.13397

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