Molecular Docking Reveals the Binding Modes of Anticancer Alkylphospholipids and Lysophosphatidylcholine within the Catalytic Domain of Cytidine Triphosphate: Phosphocholine Cytidyltransferase

Alkylphospholipids are synthetic analogues of endogenous phosphatidylcholines with a remarkable ability: induce the selective apoptosis of exponentially growing tumor cells. One hypothesis concerning their mechanism of action is the inhibition of cytidine triphosphate:phosphocholine cytidyltransferase (CCT), which would significantly suppress the phosphatidylcholine biosynthesis to trigger apoptosis. Herein, homology modeling, docking simulations, and the analyses of molecular interaction fields are used to suggest the most probable binding modes of four alkylphospholipids (edelfosine, erucylphosphocholine, perifosine, and miltefosine) and lysophosphatidylcholine at the catalytic domain of human CCT. All compounds display bind modes in agreement with the corresponding groups found in the CCT substrate, phosphocholine, while their binding strengths are increased because of the interaction of the alkyl chains with hydrophobic residues from the M domain of the protein. Analyses of the geometry of the CCT binding‐site also suggest that small groups, such as benzyl/2‐phenylethyl ethers or equivalent heterocycles, could replace the O‐methyl group in edelfosine to yield even better inhibitors. It is believed this study can guide the development of new alkylphospholipids with an improved profile for the inhibition of phosphatidylcholine biosynthesis, a critical component for cell cycle progression that can be explored in cancer chemotherapy. Practical Applications: Studies focusing on the interactions between small ligands and their protein targets are decisive for the comprehension of how conformational changes in the macromolecular structure dictates the biological activity and, consequently, how they can be explored in drug discovery. Most of the current studies on alkylphospholipids focuses on their physicochemical interactions with cholesterol and sphingolipids in lipid rafts that, because of the variability and complexity of the membrane phases, hardly can provide structural data in the X‐ray crystallography assays necessary for molecular modeling studies. Therefore, by exploring the inhibition of human cytidine triphosphate:phosphocholine cytidyltransferase as an alternative and, probably, complementary hypothesis to the membrane rafts, a helpful strategy can be provided to overcome the clinical limitations of alkylphospholipids.