Shedding Light on the Hydrolysis Mechanism of cis, trans-[Ru(dmso)₄Cl₂] Complexes and Their Interactions with DNA—A Computational Perspective

Abstract

Using several computational tools such as density functional theory analysis, docking, and MD simulations, we performed a study on cis, trans-[Ru­(II)­(dmso)4Cl2] complexes, which have therapeutic potential as antimetastatic agents, and their association with DNA. Kohn–Sham energy decomposition analysis reveals that dmso ligands have much smaller interaction energies compared to the chlorido ligands, and their substitution by aquo ligands induces an extra stabilization of the other metal–ligand bonds. Once the complex is hydrolyzed, the aquo ligands have the weakest interactions to the metallic center and therefore are more labile for substitution by a DNA atom. Molecular docking and molecular dynamics were employed to understand the complex preassociation to DNA, pointing to a higher affinity of the hydrolyzed complexes, as well as showing spontaneous binding events during the simulations. Our results are consistent with the experimentally available data that suggest a mechanism in which the complexes are quickly hydrolyzed in solution, before forming cross-links with the DNA molecule. We present a set of methods that could be used to optimize these complexes computationally, aiding in the development of new drugs based on transition metals.

Generalized Kohn‐Sham energy decomposition analysis and its applications

“…Metal‐ligand interactions play important roles in nanocrystals, molecular recognition, drug design, metalloprotein chemistry, and so on. Both GKS‐EDA and LMO‐EDA have been employed in the interpretations of various metal‐ligand interactions, which are not trivial tasks due to the inherent complexity of the arrangement of electrons in d‐ and f‐metal‐atom orbitals coupled with the various ligands.…”

“…Andriani et al presented a GKS‐EDA study at the BP86‐D3/def2‐TZVPP level for the ligand interactions in cis and trans [Ru(S‐dmso) 4 Cl 2 ]) complexes (dmso: dimethyl sulfoxide) and their hydrolyzed species . Among these ligand, chloride ligands interact more strongly with the metal center than [S‐dmso] or [O‐dmso] because of the large electrostatic term.…”

Hydrogen transfer reaction: Bond formation and bond cleavage through the eyes of interacting quantum atoms

“…In the current contribution, the analysis of the same system, hydroquinone (HQ) and the methoxy radical (Me • ), is continued with the focus on the properties of the two O-H bonds that play a crucial role in this hydrogen transfer reaction, i.e., the one that is broken O(HQ)-H and the one that is formed O(Me)-H. More precisely, the energy components of the two bonds along the intrinsic reaction path in the vicinity of the transition state are analyzed by employing interacting quantum atoms methodology, which has hitherto been widely used for the investigation of interactions between fragments in various systems. [16][17][18][19][20][21][22][23]…”