Monomeric cisplatin complexes with glutathione: Coordination modes and binding affinities

The B3LYP/LANL2DZ level of theory was used to investigate the complexes formed due to the association of two of the tautomeric forms of the cytoplasmic thiol containing tripeptide glutathione (GSH) to the post water substituted hydrolysed form of the anti-cancer drug cisplatin, [Pt(NH3)2]2+. The most energetically favored species on the resulting energy surface in the gas phase and in solution, were shown to involve Pt coordination to the dehydrogenated sulfur atom of the GSH middle residue. In these structures, electron rich groups on the GSH backbone were shown to displace the coordinating NH3 goups of cisplatin which were shown to be involved in strong hydrogen bonding within the first solvation sphere of the resulting species. Structures not involving Pt-S bonds were also shown to be energetically competitive both in the gas phase and in solution. This suggests that Pt binding within the proteome might be more homogeneous than initially thought and much less exclusively targeted towards sulfur containing ligands.