5AFV

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

Summary for 5AFV

• Entry DOI: 10.2210/pdb5afv/pdb
• Descriptor: CHOLINE KINASE ALPHA, 1,2-ETHANEDIOL, 1-benzyl-4-(benzylamino)-1H-1,2,4-triazol-4-ium, ... (4 entities in total)
• Functional Keywords: transferase, virtual screening, pharmacophore
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P35790
• Total number of polymer chains: 2
• Total formula weight: 90096.21

Authors

Serran-Aguilera, L.,Nuti, R.,Lopez-Cara, L.C.,Gallo Mezo, M.A.,Macchiarulo, A.,Entrena, A.,Hurtado-Guerrero, R. (deposition date: 2015-01-26, release date: 2015-03-18, Last modification date: 2024-01-10)

Primary citation

Serran-Aguilera, L.,Nuti, R.,Lopez-Cara, L.C.,Gallo Mezo, M.A.,Macchiarulo, A.,Entrena, A.,Hurtado-Guerrero, R.
Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase Alpha1
Mol Inform, 34:458-, 2015

PubMed Abstract: 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.

PubMed: 27490389
DOI: 10.1002/MINF.201400140

Experimental method

X-RAY DIFFRACTION (2.25 Å)