Recent progress in probing small molecule interactions with DNA

Nucleic acids are primary therapeutic targets, and understanding drug-DNA interactions is essential to the discovery of new clinical agents. In recent years, the desire to develop therapies with specific biological targets has produced new molecules that preferentially interact with complex nucleic acid sequences and structures. As such, the targeting of non-canonical nucleic acids, including DNA triplexes, G-quadruplexes, i-motifs, three-way junctions and Holliday junctions, have emerged due to their roles in gene regulation, genome stability and cellular stress responses. Characterising the interactions of these non-canonical structures with new ligands and metal complexes has led to the discovery of promising agents with therapeutic potential. Biophysical techniques including spectroscopic methods, crystallography and biomolecular assays have been critical to probing these interactions. This review describes recent advancements in the analysis of higher-order drug-DNA interactions for the rational design of targeted therapeutics.