Topology and dynamics of the interaction between 5-nitroimidazole radiosensitizers and duplex DNA studied by a combination of docking, molecular dynamic simulations and NMR spectroscopy

In spite of recent progress, cancer is still one of the most serious health problems of mankind. Recently, it has been discovered that tumor hypoxia can be exploited for selective anticancer treatment using radiosensitizers that are activated only under hypoxic conditions. The most commonly used radiosensitizers are the 5-nitroimidazole derivatives. The toxicity of bioreductive anticancer drugs, such as radiosensitizers is associated to their interaction with DNA. In this work, we have investigated the interaction between the model radiosensitizers metronizole, nimorazole and secnidazole with salmon DNA in order to get insights on the drug–macromolecule interactions. To this end, we have employed NMR techniques (PFG NMR spectra and spin–lattice relaxation rates) in combination with theoretical tools, such as docking calculations and MD simulations. Initially, results show that the δ values are not the most appropriated NMR parameters to map the interaction topology of drug–macromolecule complexes. Furthermore our data indicate that radiosensitizers, in the inactive form, interact considerably with DNA, significantly increasing its toxicity. In fact, we obtained a good agreement between that technique and docking and MD simulations. This suggests that improvements in the structures of these molecules in order to achieve new and more selective bioreductive anticancer drugs are still necessary.