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Título: | Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1 |
Autor: | Serran Aguilera, Lucia; Nuti, Roberto; López-Cara, Luisa C.; Gallo Meza, Miguel Angel; Macchiarulo, Antonio; Entrena, Antonio; Hurtado-Guerrero, Ramón CSIC ORCID | Palabras clave: | Binding Hits Crystallization Tryptophan fluorescence Virtual screening Choline kinase Pharmacophore model |
Fecha de publicación: | 1-jun-2015 | Editor: | Wiley-VCH | Citación: | Molecular Informatics 34 (6-7): 458-466 (2015) | Resumen: | Choline kinase (CK) catalyses the transfer of the ATP γ-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the α isoforms (HsCKα) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCKα biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4-(N-methylaniline)pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low μM range to HsCKα1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCKα1. | Descripción: | 10 pags, 5 figs, 1 tab | Versión del editor: | https://doi.org/10.1002/minf.201400140 | URI: | http://hdl.handle.net/10261/256223 | DOI: | 10.1002/minf.201400140 | ISSN: | 1868-1743 | E-ISSN: | 1868-1751 |
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