The Role of the DNA Backbone in Minor-Groove Ligand Binding.

Molecular recognition between ligands and nucleic acids plays a key role in therapeutic activity. Some molecules interact with DNA in a nonbonded manner through intercalation or through the DNA grooves. The recognition of minor-groove binders is attributed to a set of hydrogen-bonding interactions between the binders and the hydrogen-bond-acceptor groups on the groove floor and walls. It is commonly considered that interactions with the sugar groups of the DNA backbone are insignificant and do not contribute to the binding affinity or the specificity. However, our group has found that the deoxyribose rings have a central function in the recognition and the intercalation of metal complexes into DNA. Herein, we determined the specific interactions between the binder CGP 40215A and the minor-groove atoms, based on the local properties of electron density. We found that specific interactions between the deoxyribose moiety within the backbone of DNA and the binder are essential for molecular recognition, and they are responsible for one third of the interaction energy.