Determination of Potential Scaffolds for Human Choline Kinase α1 by Chemical Deconvolution Studies

Abstract

Dual binding modes: Combined empirical and computational studies of a series of compounds showed adenine and 1-benzyl-4-(dimethylamino)pyridinium fragments to function most efficiently in binding CHOKα1, and also determined how the latter fragment interacts with the choline binding site through two different binding modes. These data provide a basis for the future design of better and more selective inhibitors.

Pharmacophore‐Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1

“…values found in HC‐3 derivatives is that a significant fragment of these HC‐3 derivatives is exposed to the solvent and consequently does not show interactions with the enzyme. This is further supported by our docking studies (Figure 2b) and previous crystal structures in complex with these heavier compounds 8b…”

“…The majority of the molecules in this study present better L.E. than previous heavier compounds such as HC‐3, compound 12 (PDB ID: 3ZM9)8c and compound 13 (PDB ID: 4BR3)8b (Table 1). In particular hit 9 with the best K d is the second more efficient molecule with a L.E.…”

“…Overall, this compound contains 3 of the 5 moieties present in our proposed pharmacophore (Figure S4) that in turn are required to interact with the protein as described above (Figure 2e and 4a). Owing to these interactions, hit 10 shows two binding modes that allow on one hand to compete with the magnesium atom (this metal is coordinated by Asp330 and Asn311 and the phosphate groups) and the ADP phosphate groups (Figure 4b), and on the other hand to mimic the positive charge present in HC‐3,31 choline/phosphocholine, and HC‐3 derivatives such as compound 12 ,8c compound 13 8b and compound 14 8a (Figures 4b–f). In all these compounds the positive charge is key to maintain a cation‐π interaction with Trp420.…”

Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death

“…As a consequence, CKα has been proposed and validated as a molecular target for the development of novel cancer therapeutic agents 14 15 . We rationally designed several CKα inhibitors initially based on structural modifications of the Cho uptake inhibitor Hemicholinium-3 and in the crystal structure of human CKα2 isoform subsequently 16 17 18 19 20 21 22 . Our earlier results showed one compound (BR7, Figure S1 ) that was uniquely able to occupy both Cho and ATP binding sites simultaneously 20 whereas the rest of the inhibitors exclusively bound to the Cho-binding site 21 22 .…”

“…We rationally designed several CKα inhibitors initially based on structural modifications of the Cho uptake inhibitor Hemicholinium-3 and in the crystal structure of human CKα2 isoform subsequently 16 17 18 19 20 21 22 . Our earlier results showed one compound (BR7, Figure S1 ) that was uniquely able to occupy both Cho and ATP binding sites simultaneously 20 whereas the rest of the inhibitors exclusively bound to the Cho-binding site 21 22 . We have also shown recently that compound BR33 ( Figure S1 ) was able to induce local conformational changes in the Cho-binding site, which induced the aperture of an adjacent binding site 22 .…”