The famous cisplatin drug discovered by Barnett Rosenberg in 1960 was the first inorganic molecule known to specifically target and sensitize DNA and it has been used since then in cancer treatments. In that case, it is known that the DNA sensitization is performed by bridging two stacked nucleobases, and hence hampering cell replication cycle and ultimately leading to the death of cancerous cells. This process suffers from many side effects for the treated patient due to the lack of selectivity of such compound. That is why the development of new metal-based drugs for DNA sensitization, able to interact more selectively with nucleic acids moieties have been an active field during the last decades. The help of molecular modeling in this research area proved to be efficient in probing and testing interactions between nucleic acids ensembles and inorganic drugs. More specifically, the propensity of Nickel, Iron and Rhenium-based complexes to bind canonical DNA or non-double helical structures such as G-quadruplexes will be presented. First, using classical Molecular Dynamics (MD) simulations, several binding sites and orientations (minor-groove binding, intercalation, stacking) have been explored in B-DNA for octahedral metal-based drugs and G-quadruplexes for flat complexes. Then, using a recently developed protocol to model Electronic Circular Dichroism (ECD) signals of biomolecular systems using Time-Dependent Density Functional Theory (TDDFT), these binding configurations have been confirmed by matching theoretical and experimental spectrum. And finally, DNA photosensitization have been evaluated and confirmed for some of these new compounds using TDDFT at the wB97XD level of theory and hybrid QM/MM methods.

Modeling the binding interaction of inorganic drugs with DNA and G-quadruplexes

256th National Meeting (2018)

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