7nb2 | pdb_00007nb2
Crystal structure of human choline alpha in complex with an inhibitor
Structural highlights
FunctionCHKA_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.[1] Publication Abstract from PubMedIn this article we describe the identification of unprecedented ATP-competitive ChoKalpha inhibitors starting from initial hit NMS-P830 that binds to ChoKalpha in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Delta75-ChoKalpha. NMS-P830 is able to inhibit ChoKalpha 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 ChoKalpha inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKalpha with ATP-competitive compounds. Identification of unprecedented ATP-competitive choline kinase inhibitors.,Quartieri F, Nesi M, Avanzi NR, Borghi D, Casale E, Corti E, Cucchi U, Donati D, Fasolini M, Felder ER, Galvani A, Giorgini ML, Lomolino A, Menichincheri M, Orrenius C, Perrera C, Re Depaolini S, Riccardi-Sirtori F, Salsi E, Isacchi A, Gnocchi P Bioorg Med Chem Lett. 2021 Aug 18;51:128310. doi: 10.1016/j.bmcl.2021.128310. PMID:34416377[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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