An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphin-gosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and...

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Autores principales: Vettorazzi, Marcela Cristina, Angelina, Emilio Luis, Lima, Santiago, Gonec, Tomas, Otevrel, Jan, Marvanova, Pavlina, Padrtova, Tereza, Mokry, Petr, Bobal, Pavel, Acosta, Lina M., Palma, Alirio, Cobo Domingo, Justo, Bobalova, Janette, Csollei, Jozef, Malik, Ivan, Alvarez, Sergio, Spiegel, Sarah, Jampilek, Josef, Enriz, Ricardo Daniel
Formato: Artículo
Lenguaje:Inglés
Publicado: Elsevier 2025
Materias:
Inhibidores de la esfingosina quinasa 1
Virtual screening
Synthesis
Bioassays
Molecular modelling
Acceso en línea:http://repositorio.unne.edu.ar/handle/123456789/56473
Aporte de:
RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) de Universidad Nacional del Nordeste
id I48-R184-123456789-56473
record_format dspace
spelling I48-R184-123456789-564732025-03-11T14:37:00Z An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors Vettorazzi, Marcela Cristina Angelina, Emilio Luis Lima, Santiago Gonec, Tomas Otevrel, Jan Marvanova, Pavlina Padrtova, Tereza Mokry, Petr Bobal, Pavel Acosta, Lina M. Palma, Alirio Cobo Domingo, Justo Bobalova, Janette Csollei, Jozef Malik, Ivan Alvarez, Sergio Spiegel, Sarah Jampilek, Josef Enriz, Ricardo Daniel Inhibidores de la esfingosina quinasa 1 Virtual screening Synthesis Bioassays Molecular modelling Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphin-gosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaf-folds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin 1yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the differentcompounds must be refined in order to obtain an increase in the binding affinity of these ligands. 2025-03-07T13:24:24Z 2025-03-07T13:24:24Z 2017-08-10 Artículo Vettorazzi, Marcela Cristina, et al., 2017. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. European Journal of Medical Chemistry. Francia: Elsevier, vol. 139, p. 461-481. ISSN: 0223-5234. 0223-5234 http://repositorio.unne.edu.ar/handle/123456789/56473 eng https://www.sciencedirect.com/science/article/pii/S0223523417306207?via%3Dihub openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ application/pdf p. 461-481 application/pdf Elsevier Revista Europea de Química Médica, 2017, vol. 139, p. 461-481.
institution Universidad Nacional del Nordeste
institution_str I-48
repository_str R-184
collection RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
language Inglés
topic Inhibidores de la esfingosina quinasa 1
Virtual screening
Synthesis
Bioassays
Molecular modelling
spellingShingle Inhibidores de la esfingosina quinasa 1
Virtual screening
Synthesis
Bioassays
Molecular modelling
Vettorazzi, Marcela Cristina
Angelina, Emilio Luis
Lima, Santiago
Gonec, Tomas
Otevrel, Jan
Marvanova, Pavlina
Padrtova, Tereza
Mokry, Petr
Bobal, Pavel
Acosta, Lina M.
Palma, Alirio
Cobo Domingo, Justo
Bobalova, Janette
Csollei, Jozef
Malik, Ivan
Alvarez, Sergio
Spiegel, Sarah
Jampilek, Josef
Enriz, Ricardo Daniel
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
topic_facet Inhibidores de la esfingosina quinasa 1
Virtual screening
Synthesis
Bioassays
Molecular modelling
description Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphin-gosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaf-folds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin 1yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the differentcompounds must be refined in order to obtain an increase in the binding affinity of these ligands.
format Artículo
author Vettorazzi, Marcela Cristina
Angelina, Emilio Luis
Lima, Santiago
Gonec, Tomas
Otevrel, Jan
Marvanova, Pavlina
Padrtova, Tereza
Mokry, Petr
Bobal, Pavel
Acosta, Lina M.
Palma, Alirio
Cobo Domingo, Justo
Bobalova, Janette
Csollei, Jozef
Malik, Ivan
Alvarez, Sergio
Spiegel, Sarah
Jampilek, Josef
Enriz, Ricardo Daniel
author_facet Vettorazzi, Marcela Cristina
Angelina, Emilio Luis
Lima, Santiago
Gonec, Tomas
Otevrel, Jan
Marvanova, Pavlina
Padrtova, Tereza
Mokry, Petr
Bobal, Pavel
Acosta, Lina M.
Palma, Alirio
Cobo Domingo, Justo
Bobalova, Janette
Csollei, Jozef
Malik, Ivan
Alvarez, Sergio
Spiegel, Sarah
Jampilek, Josef
Enriz, Ricardo Daniel
author_sort Vettorazzi, Marcela Cristina
title An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
title_short An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
title_full An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
title_fullStr An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
title_full_unstemmed An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
title_sort integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
publisher Elsevier
publishDate 2025
url http://repositorio.unne.edu.ar/handle/123456789/56473
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