Monomeric cisplatin complexes with glutathione: Coordination modes and binding affinities

A detailed structural analysis of the complexes resulting from the association of the neutral, mono- and di-anionic forms cytoplasmic thiol containing tripeptide glutathione (GSH) to the post water substituted hydrolysed form of the anti-cancer drug cisplatin, [Pt(NH3)2]2+, in the gas phase and in solution is presented. These structures which are formed from a 1:1 molar ratio of the glutathione ligand and the Pt-drug, have been proposed as possible intermediates for several postulated disulfide bridged polymeric species. Ten gas phase structures on the [GSH − H + Pt(NH3)2]+ potential energy surface are presented and the coordination of the Pt metal is discussed. The [GSH + Pt(NH3)2]2+ potential energy surface was also explored and twelve gas phase structures on this surface are presented. In order to describe the complexes examined here in solution, water solvation effects were considered for eight and nine of the most energetically favored structures of the [GSH − H + Pt(NH3)2]+ and [GSH + Pt(NH3)2]2+ potential energy surfaces, respectively. The enthalpy and free energy, based on the most thermodynamically favored conformers of the reactants and products, for the addition reaction [Pt(NH3)2]2+ + [GSH − H]− → [GSH − H + Pt(NH3)2]+ in the gas phase at 298 K were determined to be −331.8 and −314.8 kcal mol−1, respectively. Similarly, the enthalpy and free energy of the gas phase reaction [Pt(NH3)2]2+ + GSH → [GSH + Pt(NH3)2]2+ at 298 K were determined to be −185.0 and −167.4 kcal mol−1.