5afv

Pharmacophore-based virtual screening to discover new active compounds for human choline kinase alpha1.

spinqualitylabelsall models 5afv, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5afv is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, JH5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CHKA_HUMAN] Has a key role in phospholipid biosynthesis and may contribute to tumor cell growth. Catalyzes the first step in phosphatidylcholine biosynthesis. Contributes to phosphatidylethanolamine biosynthesis. Phosphorylates choline and ethanolamine. Has higher activity with choline. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Choline kinase

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