Molecular dynamics simulation and free energy analysis of the interaction of platinum-based anti-cancer drugs with DNA

Abstract

Cisplatin and oxaliplatin are two widely-used anti-cancer drugs which covalently bind to a same location in DNA strands. Platinum agents make intrastrand and interstrand cross-links with the N7 atoms of guanine nucleotides which prevent DNA from polymerization by causing a distortion in the double helix. Molecular dynamics simulations and free energy calculations were carried out to investigate the binding of two platinum-based anti-cancer drugs with DNA. We compared the binding of these drugs which differ in their carrier ligands, and hence their potential interactions with DNA. When a platinum agent binds to nucleotides, it causes a high amount of deformation in DNA structure. To find the extent of deformation, torsion angles and base pair and groove parameters of DNA were considered. These parameters were compared with normal B-DNA which was considered as the undamaged DNA. The formation of hydrogen bonds between drugs and DNA nucleotides was examined in solution. It was shown that oxaliplatin forms more hydrogen bonds than cisplatin. Our results confirm that the structure of the platinated DNA rearranges significantly and cisplatin tries to deform DNA more than oxaliplatin. The binding free energies were also investigated to understand the affinities, types and the contributions of interactions between drugs and DNA. It was concluded that oxaliplatin tendency for binding to DNA is more than cisplatin in solvent environment. The binding free energy was calculated based on the MM/PBSA and MM/GBSA methods and the results of QM/MM calculations verified them.

Novel Complex of Zinc (II) Dichloroethylenediamine: Synthesis, Characterization, In-silico, and In-vitro Evaluation against Cervical Cancer Cells

“…Moreover, Zn(en)Cl 2 fairly bound to the binding site of the DNA during the simulation. The higher RMSD value of the complex, the more unstable the drug-DNA structural quality upon ligand binding, so the RMSD with the lowest value is preferred due to the minimal structural change during the simulation (Jalili et al, 2016).…”

Recent Developments and Applications of the MMPBSA Method

“…There were also several studies involving small ligands binding to nucleic acids. Interactions of anticancer compounds with DNA, such as cisplatin and oxaliplatin (Jalili et al, 2016 ), distamycin with the DNA minor groove (Jalili and Maddah, 2017 ), and plant alkaloid chelerythrine with the human telomere sequence (Ghosh et al, 2015 ) were reported. Aminobenzimidazole binding to an internal ribosome entry site was studied for its anti-hepatitis C virus effect (Henriksen et al, 2014 ).…”