Multilayered Modelling of the Metallation of Biological Targets

The unique property of metals – the remarkable ability to modulate the electronic structure of both metal center and bound ligands – is the reason for their omnipresence in enzymes and in metal-coordinating biological factors. Modern metallodrug chemistry began with the serendipitous unveiling of the antitumour properties of cisplatin, followed by an avalanche of synthesized novel metallodrugs. The metallation of biological targets has then become a new paradigm in the field of bioinorganic chemistry, and a plethora of computational approaches have been developed and utilized to ease the detailed comprehension of its mechnisms with a focus on medical applications. Studies of the electronic structure of metallodrugs and of the coordination of metal elements with biomolecular ligands, as well as an accurate description of both thermodynamics and kinetics of reactions with biomolecules, are crucial for development of novel metallodrugs with improved therapeutic profiles. Here, we provide an account of the application of multilayered computational schemes developed in our group for the study of processes leading and/or culminating with the metallation of biomolecules, the key step in the mechanism of action of metallodrugs.