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Artículo

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

Vettorazzi, Marcela CristinaIcon ; Angelina, Emilio LuisIcon ; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; Marvanova, Pavlina; Padrtova, Tereza; Mokry, Petr; Bobal, Pavel; Acosta, Lina M.; Palma, Alirio; Cobo, Justo; Bobalova, Janette; Csollei, Jozef; Malik, Ivan; Alvarez, Sergio EduardoIcon ; Spiegel, Sarah; Jampilek, Josef; Enriz, Ricardo DanielIcon
Fecha de publicación: 10/2017
Editorial: Elsevier France-editions Scientifiques Medicales Elsevier
Revista: European Journal of Medical Chemistry
ISSN: 0223-5234
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
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Resumen

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-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 scaffolds (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[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)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 different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.
Palabras clave: Bioassays , Molecular Modelling , Sphingosine Kinase 1 Inhibitors , Synthesis , Virtual Screening
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/37958
URL: https://www.sciencedirect.com/science/article/pii/S0223523417306207
DOI: http://dx.doi.org/10.1016/j.ejmech.2017.08.017
Colecciones
Articulos(IQUIBA-NEA)
Articulos de INSTITUTO DE QUIMICA BASICA Y APLICADA DEL NORDESTE ARGENTINO
Citación
Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; et al.; An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors; Elsevier France-editions Scientifiques Medicales Elsevier; European Journal of Medical Chemistry; 139; 10-2017; 461-481
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