7NB3

Crystal structure of human choline alpha in complex with an inhibitor

This is a non-PDB format compatible entry.

Summary for 7NB3

• Entry DOI: 10.2210/pdb7nb3/pdb
• Descriptor: Choline kinase alpha, 4-(6-azanyl-2-pyridin-4-yl-purin-9-yl)-~{N}-(3-methoxyphenyl)cyclohexane-1-carboxamide, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: transferase, phosphatidylcholine, inhibitor complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 91673.55

Authors

Casale, E.,Fasolini, M. (deposition date: 2021-01-25, release date: 2021-10-13, Last modification date: 2024-01-31)

Primary citation

Quartieri, F.,Nesi, M.,Avanzi, N.R.,Borghi, D.,Casale, E.,Corti, E.,Cucchi, U.,Donati, D.,Fasolini, M.,Felder, E.R.,Galvani, A.,Giorgini, M.L.,Lomolino, A.,Menichincheri, M.,Orrenius, C.,Perrera, C.,Re Depaolini, S.,Riccardi-Sirtori, F.,Salsi, E.,Isacchi, A.,Gnocchi, P.
Identification of unprecedented ATP-competitive choline kinase inhibitors.
Bioorg.Med.Chem.Lett., 51:128310-128310, 2021

PubMed Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.

PubMed: 34416377
DOI: 10.1016/j.bmcl.2021.128310

Experimental method

X-RAY DIFFRACTION (2 Å)