Anti-cancer alkylphospholipids and their binding-mode with CCT enzyme

Alkylphospholipids are synthetic derivatives of endogenous phosphatidylcholines, possessing the ability of inducing apoptosis in tumor cells. [1]. It is possible that these compounds suppress the biosynthesis of phosphatidylcholine trough the CTP:phosphocholine cytidyltransferase (CCT) enzyme, promoting the apoptosis of cancer cells [2,3]. Homology modelling, docking simulations and the analyses of molecular interaction fields were used to suggest the most likely binding modes of four alkylphospholipids (edelfosine, erucylphosphocholine, perifosine and miltefosine) at the catalytic domain of human CCT (h-CCT).
The docking simulations indicates the methyl group of edelfosine is not involved in relevant interactions with h-CCT, substitution of this group could yield analogues with improved affinities for the enzyme. Some small groups, such as benzyl/2-phenylethyl ethers or similar heterocycles, may replace the O-methyl group in edelfosine for better inhibitors. Therefore, this study may lead to a potential target for cancer chemotherapy, as from the development of alkyl phospholipids with improved inhibition profiles.