Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach

Autores
Bombasaro, José Abel; Barrera Guisasola, Exequiel Ernesto; Masman, Marcelo Fabricio; Rodríguez, Ana María
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Acetogenins are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Elucidation of the dynamic function of the alkyl spacer linking the two toxophores (i.e., the hydroxylated tetrahydrofuran and the γ-lactone rings) is critical for fully understanding their inhibition mechanism. To this end, using molecular dynamics simulations a structure-activity relationship study of a series of acetogenins was performed for the first time using this approach. Our results clearly indicated that both, the length and the molecular flexibility of the spacer, were crucial for taking an active conformation. A partially folded conformation with an optimal length (bis-tetrahydrofuran rings and 13 carbon atoms) of about 16 Å with a high molecular flexibility might depict an active form of the spacer. In addition, we demonstrated that the bis-tetrahydrofuran derivatives are able to overcome the shortage of the length of the spacer more efficiently than the mono-tetrahydrofuran derivatives with the help of the additional tetrahydrofuran, which acts as a pseudospacer. Our results obtained from molecular dynamics calculations supported the use of a combined decane/water system as a good solvent model to simulate the biological environment of acetogenins acting as inhibitor of complex I.
Fil: Bombasaro, José Abel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Barrera Guisasola, Exequiel Ernesto. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Masman, Marcelo Fabricio. University of Groningen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rodríguez, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Materia
Acetogenins
Molecular Dynamics
Sar
Decane/Water Interface
Complex I Inhibitors
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:11336/26777
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/26777
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approachBombasaro, José AbelBarrera Guisasola, Exequiel ErnestoMasman, Marcelo FabricioRodríguez, Ana MaríaAcetogeninsMolecular DynamicsSarDecane/Water InterfaceComplex I Inhibitorshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Acetogenins are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Elucidation of the dynamic function of the alkyl spacer linking the two toxophores (i.e., the hydroxylated tetrahydrofuran and the γ-lactone rings) is critical for fully understanding their inhibition mechanism. To this end, using molecular dynamics simulations a structure-activity relationship study of a series of acetogenins was performed for the first time using this approach. Our results clearly indicated that both, the length and the molecular flexibility of the spacer, were crucial for taking an active conformation. A partially folded conformation with an optimal length (bis-tetrahydrofuran rings and 13 carbon atoms) of about 16 Å with a high molecular flexibility might depict an active form of the spacer. In addition, we demonstrated that the bis-tetrahydrofuran derivatives are able to overcome the shortage of the length of the spacer more efficiently than the mono-tetrahydrofuran derivatives with the help of the additional tetrahydrofuran, which acts as a pseudospacer. Our results obtained from molecular dynamics calculations supported the use of a combined decane/water system as a good solvent model to simulate the biological environment of acetogenins acting as inhibitor of complex I.Fil: Bombasaro, José Abel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaFil: Barrera Guisasola, Exequiel Ernesto. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Masman, Marcelo Fabricio. University of Groningen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; ArgentinaBentham Science Publishers2013-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/26777Bombasaro, José Abel; Barrera Guisasola, Exequiel Ernesto; Masman, Marcelo Fabricio; Rodríguez, Ana María; Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach; Bentham Science Publishers; Medicinal Chemistry; 9; 7; 11-2013; 926-9371573-40641875-6638CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/114846/articleinfo:eu-repo/semantics/altIdentifier/doi/10.2174/1573406411309070006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:47:13Zoai:ri.conicet.gov.ar:11336/26777instacron: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 10:47:13.612CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
title Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
spellingShingle Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
Bombasaro, José Abel
Acetogenins
Molecular Dynamics
Sar
Decane/Water Interface
Complex I Inhibitors
title_short Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
title_full Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
title_fullStr Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
title_full_unstemmed Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
title_sort Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach
dc.creator.none.fl_str_mv Bombasaro, José Abel
Barrera Guisasola, Exequiel Ernesto
Masman, Marcelo Fabricio
Rodríguez, Ana María
author Bombasaro, José Abel
author_facet Bombasaro, José Abel
Barrera Guisasola, Exequiel Ernesto
Masman, Marcelo Fabricio
Rodríguez, Ana María
author_role author
author2 Barrera Guisasola, Exequiel Ernesto
Masman, Marcelo Fabricio
Rodríguez, Ana María
author2_role author
author
author
dc.subject.none.fl_str_mv Acetogenins
Molecular Dynamics
Sar
Decane/Water Interface
Complex I Inhibitors
topic Acetogenins
Molecular Dynamics
Sar
Decane/Water Interface
Complex I Inhibitors
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Acetogenins are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Elucidation of the dynamic function of the alkyl spacer linking the two toxophores (i.e., the hydroxylated tetrahydrofuran and the γ-lactone rings) is critical for fully understanding their inhibition mechanism. To this end, using molecular dynamics simulations a structure-activity relationship study of a series of acetogenins was performed for the first time using this approach. Our results clearly indicated that both, the length and the molecular flexibility of the spacer, were crucial for taking an active conformation. A partially folded conformation with an optimal length (bis-tetrahydrofuran rings and 13 carbon atoms) of about 16 Å with a high molecular flexibility might depict an active form of the spacer. In addition, we demonstrated that the bis-tetrahydrofuran derivatives are able to overcome the shortage of the length of the spacer more efficiently than the mono-tetrahydrofuran derivatives with the help of the additional tetrahydrofuran, which acts as a pseudospacer. Our results obtained from molecular dynamics calculations supported the use of a combined decane/water system as a good solvent model to simulate the biological environment of acetogenins acting as inhibitor of complex I.
Fil: Bombasaro, José Abel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
Fil: Barrera Guisasola, Exequiel Ernesto. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Masman, Marcelo Fabricio. University of Groningen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rodríguez, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química; Argentina
description Acetogenins are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Elucidation of the dynamic function of the alkyl spacer linking the two toxophores (i.e., the hydroxylated tetrahydrofuran and the γ-lactone rings) is critical for fully understanding their inhibition mechanism. To this end, using molecular dynamics simulations a structure-activity relationship study of a series of acetogenins was performed for the first time using this approach. Our results clearly indicated that both, the length and the molecular flexibility of the spacer, were crucial for taking an active conformation. A partially folded conformation with an optimal length (bis-tetrahydrofuran rings and 13 carbon atoms) of about 16 Å with a high molecular flexibility might depict an active form of the spacer. In addition, we demonstrated that the bis-tetrahydrofuran derivatives are able to overcome the shortage of the length of the spacer more efficiently than the mono-tetrahydrofuran derivatives with the help of the additional tetrahydrofuran, which acts as a pseudospacer. Our results obtained from molecular dynamics calculations supported the use of a combined decane/water system as a good solvent model to simulate the biological environment of acetogenins acting as inhibitor of complex I.
publishDate 2013
dc.date.none.fl_str_mv 2013-11
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/11336/26777
Bombasaro, José Abel; Barrera Guisasola, Exequiel Ernesto; Masman, Marcelo Fabricio; Rodríguez, Ana María; Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach; Bentham Science Publishers; Medicinal Chemistry; 9; 7; 11-2013; 926-937
1573-4064
1875-6638
CONICET Digital
CONICET
url http://hdl.handle.net/11336/26777
identifier_str_mv Bombasaro, José Abel; Barrera Guisasola, Exequiel Ernesto; Masman, Marcelo Fabricio; Rodríguez, Ana María; Dynamic function of the Alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I: a molecular dynamics simulation approach; Bentham Science Publishers; Medicinal Chemistry; 9; 7; 11-2013; 926-937
1573-4064
1875-6638
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/114846/article
info:eu-repo/semantics/altIdentifier/doi/10.2174/1573406411309070006
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 Bentham Science Publishers
publisher.none.fl_str_mv Bentham Science Publishers
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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