Potential choline kinase inhibitors: a molecular modeling study of bis-quinolinium compounds

Abstract

Choline kinase (ChoK) is reported to involve in cell signaling pathways and cell growth by regulating the intermediate, phosphocholine (PCho), which is the first step to biosynthesis a membrane phospholipid, phosphatidylcholine. The PCho levels are overexpressed due to elevated activation of the protein under carcinogenesis conditions. ChoK has thus evolved as a novel target for various cancers and a range of compounds has been reported in this course as potent ChoK inhibitors. However, not much information is known about the binding site of the inhibitors. Therefore, we ventured to unravel the possible binding site of 39 bis-quinolinium inhibitors from which the structural requirement for better protein–ligand complex was delved. Molecular docking and 3D-QSAR studies namely comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on the series. The knowledge of the active site was obtained from the site id search and molcad surface calculations of Sybyl, which was further considered for docking studies. In 3D-QSAR, the best predictions were obtained from the model where 29 compounds were considered in the training set and remaining 10 in the test set. The best CoMFA statistics were obtained with r² of 0.99 and q² of 0.81 while, CoMSIA was resulted with r² of 0.98 and q² of 0.77. A comparative analysis was done with the resulted 3D-QSAR maps and the docked poses by overlaying the maps on the active site residues. Since, there is no reported ligand co-crystallized structure of ChoK the present study provides valuable clues on the binding conformation of the ligand and its interactions with the active site.