5afv

Publication Abstract from PubMed

Choline kinase (CK) catalyses the transfer of the ATP gamma-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 alpha isoforms (HsCKalpha) 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 HsCKalpha 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 muM range to HsCKalpha1. 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 HsCKalpha1.

Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase alpha1.,Serran-Aguilera L, Nuti R, Lopez-Cara LC, Mezo MA, Macchiarulo A, Entrena A, Hurtado-Guerrero R Mol Inform. 2015 Jun;34(6-7):458-66. doi: 10.1002/minf.201400140. Epub 2015 Jun, 18. PMID:27490389^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.