Interaction of Platinum-based Drugs with Proteins: An Overview Representative Crystallographic Studies

Pt-based drugs are widely used in clinics for the treatment of cancer. The mechanism of action of these molecules relies on their interaction with DNA. However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles. Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process. Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, are briefly described and comparatively examined. Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that occur in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct. In the metallated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing labile ligands.

Automated summary

Pt-based drugs are widely used in cancer treatment, with their mechanisms of action depending on interactions with DNA. Proteins' recognition of these metal compounds plays a crucial role in pharmacokinetics, side effects, and overall pharmacological profiles. Single crystal X-ray diffraction studies provide valuable insights into the molecular mechanisms underlying this process, revealing that metal ligands and non-covalent interactions drive the reaction of Pt compounds with proteins. Metalated protein structures coordinate few protein side chains upon releasing labile ligands, highlighting the importance of early-stage non-covalent interactions in defining the structure of the final Pt-protein adduct.