Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents

Autores
Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Tosso, Rodrigo David; Adarvez Feresin, Camila Wadía; Garibotto, Francisco Matías; Cobo, Justo; Enriz, Ricardo Daniel
Año de publicación
2023
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
We report here the virtual screening design, synthesis, and activity of eight new inhibitors of SphK1. For this study, we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effects against sphingosine kinase 1(SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell lines tested, with GI 50 below 5 μM, being (5) the most promising with TGI below 10 μM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolonine hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study of the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modelinganalysis was carried out by using combined techniques: docking calculations, MD simulations, and QTAIM analysis. In this study wealso included PF543, as a reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.
Fil: Vettorazzi, Marcela Cristina. 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: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina
Fil: Tosso, Rodrigo David. 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: Adarvez Feresin, Camila Wadía. 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: Garibotto, Francisco Matías. 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: Cobo, Justo. Universidad de Jaén; España
Fil: Enriz, Ricardo Daniel. 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
LI Reunion Anual Sociedad Argentina de Biofísica
Córdoba
Argentina
Sociedad Argentina de Biofísica
Materia
INHIBITORS
SPHINGOSINE
MOLECULAR MODELLING
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:11336/266256
Acceder
id CONICETDig_053dc741e6d68dbbf1b28cc57ec64748
oai_identifier_str oai:ri.conicet.gov.ar:11336/266256
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agentsVettorazzi, Marcela CristinaAngelina, Emilio LuisTosso, Rodrigo DavidAdarvez Feresin, Camila WadíaGaribotto, Francisco MatíasCobo, JustoEnriz, Ricardo DanielINHIBITORSSPHINGOSINEMOLECULAR MODELLINGhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1We report here the virtual screening design, synthesis, and activity of eight new inhibitors of SphK1. For this study, we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effects against sphingosine kinase 1(SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell lines tested, with GI 50 below 5 μM, being (5) the most promising with TGI below 10 μM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolonine hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study of the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modelinganalysis was carried out by using combined techniques: docking calculations, MD simulations, and QTAIM analysis. In this study wealso included PF543, as a reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.Fil: Vettorazzi, Marcela Cristina. 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: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; ArgentinaFil: Tosso, Rodrigo David. 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: Adarvez Feresin, Camila Wadía. 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: Garibotto, Francisco Matías. 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: Cobo, Justo. Universidad de Jaén; EspañaFil: Enriz, Ricardo Daniel. 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; ArgentinaLI Reunion Anual Sociedad Argentina de BiofísicaCórdobaArgentinaSociedad Argentina de BiofísicaSociedad Argentina de Biofísica2023info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266256Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents; LI Reunion Anual Sociedad Argentina de Biofísica; Córdoba; Argentina; 2023; 104-104CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/publicaciones/libros-de-resumenes/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T11:54:21Zoai:ri.conicet.gov.ar:11336/266256instacron: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:34982025-10-29 11:54:21.726CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
title Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
spellingShingle Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
Vettorazzi, Marcela Cristina
INHIBITORS
SPHINGOSINE
MOLECULAR MODELLING
title_short Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
title_full Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
title_fullStr Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
title_full_unstemmed Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
title_sort Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents
dc.creator.none.fl_str_mv Vettorazzi, Marcela Cristina
Angelina, Emilio Luis
Tosso, Rodrigo David
Adarvez Feresin, Camila Wadía
Garibotto, Francisco Matías
Cobo, Justo
Enriz, Ricardo Daniel
author Vettorazzi, Marcela Cristina
author_facet Vettorazzi, Marcela Cristina
Angelina, Emilio Luis
Tosso, Rodrigo David
Adarvez Feresin, Camila Wadía
Garibotto, Francisco Matías
Cobo, Justo
Enriz, Ricardo Daniel
author_role author
author2 Angelina, Emilio Luis
Tosso, Rodrigo David
Adarvez Feresin, Camila Wadía
Garibotto, Francisco Matías
Cobo, Justo
Enriz, Ricardo Daniel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv INHIBITORS
SPHINGOSINE
MOLECULAR MODELLING
topic INHIBITORS
SPHINGOSINE
MOLECULAR MODELLING
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv We report here the virtual screening design, synthesis, and activity of eight new inhibitors of SphK1. For this study, we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effects against sphingosine kinase 1(SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell lines tested, with GI 50 below 5 μM, being (5) the most promising with TGI below 10 μM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolonine hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study of the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modelinganalysis was carried out by using combined techniques: docking calculations, MD simulations, and QTAIM analysis. In this study wealso included PF543, as a reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.
Fil: Vettorazzi, Marcela Cristina. 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: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina
Fil: Tosso, Rodrigo David. 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: Adarvez Feresin, Camila Wadía. 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: Garibotto, Francisco Matías. 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: Cobo, Justo. Universidad de Jaén; España
Fil: Enriz, Ricardo Daniel. 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
LI Reunion Anual Sociedad Argentina de Biofísica
Córdoba
Argentina
Sociedad Argentina de Biofísica
description We report here the virtual screening design, synthesis, and activity of eight new inhibitors of SphK1. For this study, we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effects against sphingosine kinase 1(SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell lines tested, with GI 50 below 5 μM, being (5) the most promising with TGI below 10 μM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolonine hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study of the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modelinganalysis was carried out by using combined techniques: docking calculations, MD simulations, and QTAIM analysis. In this study wealso included PF543, as a reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/266256
Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents; LI Reunion Anual Sociedad Argentina de Biofísica; Córdoba; Argentina; 2023; 104-104
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266256
identifier_str_mv Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents; LI Reunion Anual Sociedad Argentina de Biofísica; Córdoba; Argentina; 2023; 104-104
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/publicaciones/libros-de-resumenes/
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.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
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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