Understanding how an anticancer complex binds DNA has brought metal-metal based antitumour drugs one step closer. Dirk Deubel at the Swiss Federal Institute of Technology Zurich (ETH Zurich), Switzerland, and Helen Chifotides at Texas A&M University, in College Station, US, have calculated the binding mechanism of complex dirhodium tetracarboxylate to the DNA base guanine.

Increasing attention is being paid to metal-metal based anticancer complexes as potential inhibitors of DNA replication. 'DNA-complex binding is believed to be the key reaction responsible for the anticancer activity of these compounds,' said Judit Sponer, a specialist in computational analysis of metallopharmaceuticals at the Academy of Sciences of the Czech Republic in Brno. Whilst the reactants and products in this step can be identified through conventional experiments, the mechanism of the interaction is not always clear. Clarifying the reaction mechanism is useful for redesigning ligands to improve the effectiveness of potential drugs.

Using a combination of computational approaches, Deubel and Chifotides managed to identify the possible intermediates in the DNA-complex binding reaction and the transition states between them. The team then calculated the free energies of these states to discover the lowest energy pathway. Their results showed that the reaction proceeds through five intermediates and involves guanine migrating from an axial to an equatorial position in the complex. This is a 'very detailed description of the full reaction pathway,' said Sponer.

Looking to the future, Deubel said that the challenge was to 'tune the ligands at the metal-metal core to optimise the interplay between lability [of the ligands] and robustness of the di-metal core. Potentially, computational approaches could be used to screen ligands by predicting the energy of intermediates and transition states in systematic studies.'  

Russell Johnson