Targeting G-quadruplex with Small Molecules: An NMR View

Abstract

G-quadruplexes are emerging as important drug targets in anticancer research. They possess a remarkable structural polymorphism in solution, making NMR spectroscopy a unique tool to investigate structure and dynamics of this class of biomolecules. Here, an overview of G-quadruplex (G4) structural polymorphism and NMR structures in the holo and apo state is given, as well as state-of-the-art NMR methods to investigate G4-ligand interactions. The choice of methods strongly depends on the exchange regime in which a ligand is binding, which is presented in detail. Another focus is given to the assignment of G4-ligand complexes to enable structure calculation. The number of NMR structures of ligands bound to G4 is still scarce: while there is evidence for ligands binding to the groove of G4s, most of the G4-ligand NMR structures reported to date show the ligand stacking on a terminal G-quartet. Further, in the presence of 3′- and 5′-flanking nucleotides forming capping structures, major structural changes in these regions are observed to accommodate the ligand, highlighting the importance of structural data to enable rational drug design. The data presented in this review highlight the importance of investigating this class of complexes and provide useful tools for structure-based drug design.