Understanding the role of hydrogen bonds in destruction of DNA by screening interactions of Flutamide anticancer drug with nucleotides bases: DFT perspective, MD simulation and free energy calculation

In the present work, we perform comprehensive theoretical calculations in order to examine interaction between Flutamide (FLU) anticancer drug and the nucleobases in the water and gaseous phases. The energetic, geometric and topological properties of Flutamide molecule interacting with four nucleotides bases, such as cytosine, thymine, uracil and guanine were studied from molecular point of view by means of density functional theory (DFT) at M06-2X /6-311++G** and CAM-B3LYP/6-311++G** levels of theory. Obtained results exhibit that interaction of the drug molecule and the nucleobases is favorable and all of the designed complexes are stable. Our computations showed that the formation of hydrogen bonds (HB) between the Flutamide atoms and bases molecules plays a main role in destruction of DNA. The Bader's quantum theory of atoms in molecules (AIM) and natural bond orbital (NBO) analysis have been employed to acquire the strength of hydrogen bonds in the intermolecular interactions. Furthermore, molecular dynamics (MD) simulation and free energy calculation are performed to investigate the interaction of the drug molecule and DNA. The obtained results are in with line DFT results and confirm that the interaction of the drug molecule with cytosine and guanine is stronger than the other base molecules. Our findings indicate that quantum mechanical calculations and molecular dynamics simulation can be successfully employed to interpret the electronic and structural features of the interactions between the drug and nucleobases.