Fragment screening and structure-based design of adrenaline synthesis inhibitors
Jansson Martin, Nyssa Drinkwater, C.L. Gee, Michael J. McLeish, Gary L. Grunewald · Acta Crystallographica Section A Foundations of Crystallography · 2008
Choline kinase (ChoK) catalyzes the ATP-dependent phosphorylation of choline, the first committed step in the CDP-choline pathway for the biosynthesis of phosphatidylcholine.Overexpression and increased activity of one of the human ChoK isoforms, ChoK alpha have been constitutively reported in malignant cells and tumour tissues.This suggests that the enzyme plays a relevant role in tumorigenesis.Some sets of in vitro and in vivo experiments confirmed that ChoK inhibition is one of the potential novel strateges for the development of new antiproliferative and anticancer drugs.The importance of ChoK for the regulation of cell proliferation has been studied by using an inhibitor hemicholinium-3 (HC-3), which was initially characterized as a lethal, respiratory paralytic agent.Most of the ChoK inhibitors introduced so far are the chemically modified derivatives based on the structure of HC-3.Crystal structures of HC-3 bound human ChoK alpha were determinded with and without ADP.In the crystal structures, HC-3 molecule was well accommodated between the N and C-terminal lobes of ChoK protein, and its one end was placed on the same binding site as a substrate choline, while the other end partially exposed to the solvent.The inhibitor molecule was stabilized mainly through the hydrophobic interactions contributed by the C-terminal lobe.These 3D information provides the first molecular detailed view concerning the mode of inhibitory action and expand our understanding of the factors governing selectivity.