Title:Interactions of Non-Phosphorous Glycerolipids with DNA: Energetics, Molecular Docking and Topoisomerase I Attenuation
Volume: 16
Issue: 3
Author(s): Valery Y. Grinberg, Vladimir B. Tsvetkov, Alina A. Markova, Lyubov G. Dezhenkova, Tatiana V. Burova, Natalia V. Grinberg, Alexander S. Dubovik, Natalia V. Plyavnik and Alexander A. Shtil
Affiliation:
Keywords:
DNA, drug-target interaction, molecular modeling, non-phosphorous glycerolipids, topoisomerase I.
Abstract: The phosphorus-containing glycerolipid based antitumor drugs (edelfosine as a prototype) are currently
in clinical trials. To avoid the use of potentially harmful phosphoric reagents in the preparation of biologically
active glycerolipids, and to obtain the compounds without the phosphoester bond cleavable inside the cells, we
developed the synthesis of non-phosphorous glycerolipids (NPGLs) with neutral or cationic polar ‘heads’. In this
study, we analyzed the ability of novel NPGLs L1-L5 to interact with duplex DNA and interfere with the DNA modifying enzyme
topoisomerase I (topo I). In cell-free systems, NPGLs formed highly affine complexes with DNA. Molecular docking revealed that
NPGLs fitted very well into the DNA minor groove. Compounds L2 (with two long hydrophobic ‘tails’) and L4 (with ethylimidazolium
cationic group), the most affine DNA binders, showed the best calculated energies of complex formation with DNA and topo I. The
models demonstrated the binding of NPGLs to the topo I site known for interaction with conventional inhibitors. Each NPGL attenuated
the topo I mediated unwinding of supercoiled DNA. Again, L2 and, to a lesser extent, L4 were the most potent topo I inhibitors. Thus,
NPGLs with polar ‘heads’ emerge as a new class of DNA ligands and interfacial topo I antagonists.
