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@article{1726860,
author = {Vettorazzi, M and Angelina, E and Lima, S and Goněc, Tomáš and Otevřel, Jan and Marvanová, Pavlína and Padrtová, Tereza and Mokrý, Petr and Bobáľ, Pavel and Acosta, LM and Palma, A and Cobo, J and Bobáľová, Janette and Csöllei, Jozef and Malík, Ivan and Alvarez, S and Spiegel, S and Jampilek, J and Enriz, RD},
article_location = {PARIS},
doi = {http://dx.doi.org/10.1016/j.ejmech.2017.08.017},
keywords = {Sphingosine kinase 1 inhibitors; Virtual screening; Synthesis; Bioassays; Molecular modelling},
language = {eng},
issn = {0223-5234},
journal = {European Journal of Medicinal Chemistry},
title = {An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors},
volume = {139},
year = {2017}
}
TY - JOUR
ID - 1726860
AU - Vettorazzi, M - Angelina, E - Lima, S - Goněc, Tomáš - Otevřel, Jan - Marvanová, Pavlína - Padrtová, Tereza - Mokrý, Petr - Bobáľ, Pavel - Acosta, LM - Palma, A - Cobo, J - Bobáľová, Janette - Csöllei, Jozef - Malík, Ivan - Alvarez, S - Spiegel, S - Jampilek, J - Enriz, RD
PY - 2017
TI - An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
JF - European Journal of Medicinal Chemistry
VL - 139
SP - 461-481
EP - 461-481
PB - ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
SN - 02235234
KW - Sphingosine kinase 1 inhibitors
KW - Virtual screening
KW - Synthesis
KW - Bioassays
KW - Molecular modelling
N2 - 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)ethyliphenyl}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. (C) 2017 Elsevier Masson SAS. All rights reserved.
ER -
VETTORAZZI, M, E ANGELINA, S LIMA, Tomáš GONĚC, Jan OTEVŘEL, Pavlína MARVANOVÁ, Tereza PADRTOVÁ, Petr MOKRÝ, Pavel BOBÁĽ, LM ACOSTA, A PALMA, J COBO, Janette BOBÁĽOVÁ, Jozef CSÖLLEI, Ivan MALÍK, S ALVAREZ, S SPIEGEL, J JAMPILEK a RD ENRIZ. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. \textit{European Journal of Medicinal Chemistry}. PARIS: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017, roč.~139, s.~461-481. ISSN~0223-5234. Dostupné z: https://dx.doi.org/10.1016/j.ejmech.2017.08.017.
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