Binding free energy of selected anticancer compounds to DNA--theoretical calculations

Many studies have elucidated structures and thermodynamics of complexes formed by different ligands with DNA. However, in most cases structural and free energy binding studies were not correlated with each other because of the problem of identifying which experimental free energy of binding corresponds to which experimental DNA-ligand structure. In the present work, Poisson-Boltzmann and solvent-accessible surface area methods were used to predict unknown modes of interaction between DNA and three different ligands: mitoxantrone and two pyrimidoacridine derivatives. In parallel, experimental measurements of binding free energy for the studied complexes were performed to compare experimental and calculated values. Our studies showed that the calculated values of free energy are only close to experimental data for some models of interaction between ligands and DNA. Based on this correlation, the most likely models of DNA-ligand complexes were postulated: (i) mitoxantrone and one derivative of pyrimidoacridine, both with two charged side chains, intercalate from the minor groove of DNA and bind with both chains in this groove; (ii) pyrimidoacridine, with only one side chain, very likely does not intercalate into DNA at all. Additionally, the non-electrostatic and electrostatic parts of the calculated binding free energy for the DNA-ligands studied are discussed.