Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase

Autores
Paz, Paula B.; Vega Hissi, Esteban Gabriel; Andrada, Matias Fernando; Estrada, Mario R.; Garro Martinez, Juan Ceferino
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC50. In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DGbind). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (Rtest) of 0.714 and a standard deviation (Stest) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.
Fil: Paz, Paula B.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Vega Hissi, Esteban Gabriel. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Andrada, Matias Fernando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Estrada, Mario R.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Garro Martinez, Juan Ceferino. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Materia
Inhibitory Activity
Leukotriene A4 Hydrolase
Molecular Docking
N-Alkyl Glycine Amides
Qsar
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:11336/6984
Acceder
id CONICETDig_95a172d5049421181c797fa9f07a3e04
oai_identifier_str oai:ri.conicet.gov.ar:11336/6984
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolasePaz, Paula B.Vega Hissi, Esteban GabrielAndrada, Matias FernandoEstrada, Mario R.Garro Martinez, Juan CeferinoInhibitory ActivityLeukotriene A4 HydrolaseMolecular DockingN-Alkyl Glycine AmidesQsarhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC50. In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DGbind). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (Rtest) of 0.714 and a standard deviation (Stest) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.Fil: Paz, Paula B.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; ArgentinaFil: Vega Hissi, Esteban Gabriel. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Andrada, Matias Fernando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; ArgentinaFil: Estrada, Mario R.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; ArgentinaFil: Garro Martinez, Juan Ceferino. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaSpringer2014-07info: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/11336/6984Paz, Paula B.; Vega Hissi, Esteban Gabriel; Andrada, Matias Fernando; Estrada, Mario R.; Garro Martinez, Juan Ceferino; Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase; Springer; Medicinal Chemistry Research; 24; 2; 7-2014; 496-5041054-2523enginfo:eu-repo/semantics/altIdentifier/ark/10.1007/s00044-014-1121-yinfo:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/doi/10.1007/s00044-014-1121-yinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:39:19Zoai:ri.conicet.gov.ar:11336/6984instacron: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:34982025-10-15 14:39:19.827CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
title Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
spellingShingle Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
Paz, Paula B.
Inhibitory Activity
Leukotriene A4 Hydrolase
Molecular Docking
N-Alkyl Glycine Amides
Qsar
title_short Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
title_full Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
title_fullStr Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
title_full_unstemmed Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
title_sort Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase
dc.creator.none.fl_str_mv Paz, Paula B.
Vega Hissi, Esteban Gabriel
Andrada, Matias Fernando
Estrada, Mario R.
Garro Martinez, Juan Ceferino
author Paz, Paula B.
author_facet Paz, Paula B.
Vega Hissi, Esteban Gabriel
Andrada, Matias Fernando
Estrada, Mario R.
Garro Martinez, Juan Ceferino
author_role author
author2 Vega Hissi, Esteban Gabriel
Andrada, Matias Fernando
Estrada, Mario R.
Garro Martinez, Juan Ceferino
author2_role author
author
author
author
dc.subject.none.fl_str_mv Inhibitory Activity
Leukotriene A4 Hydrolase
Molecular Docking
N-Alkyl Glycine Amides
Qsar
topic Inhibitory Activity
Leukotriene A4 Hydrolase
Molecular Docking
N-Alkyl Glycine Amides
Qsar
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC50. In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DGbind). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (Rtest) of 0.714 and a standard deviation (Stest) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.
Fil: Paz, Paula B.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Vega Hissi, Esteban Gabriel. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Andrada, Matias Fernando. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Estrada, Mario R.. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina
Fil: Garro Martinez, Juan Ceferino. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica. Area de Quimica Fisica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
description The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC50. In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DGbind). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (Rtest) of 0.714 and a standard deviation (Stest) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.
publishDate 2014
dc.date.none.fl_str_mv 2014-07
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/11336/6984
Paz, Paula B.; Vega Hissi, Esteban Gabriel; Andrada, Matias Fernando; Estrada, Mario R.; Garro Martinez, Juan Ceferino; Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase; Springer; Medicinal Chemistry Research; 24; 2; 7-2014; 496-504
1054-2523
url http://hdl.handle.net/11336/6984
identifier_str_mv Paz, Paula B.; Vega Hissi, Esteban Gabriel; Andrada, Matias Fernando; Estrada, Mario R.; Garro Martinez, Juan Ceferino; Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase; Springer; Medicinal Chemistry Research; 24; 2; 7-2014; 496-504
1054-2523
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/ark/10.1007/s00044-014-1121-y
info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/doi/10.1007/s00044-014-1121-y
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 Springer
publisher.none.fl_str_mv Springer
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 13.221938

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