The triazatruxene derivative azatrux binds to the parallel form of the human telomeric G-quadruplex under molecular crowding conditions: Biophysical and molecular modeling studies

The present study has employed a combination of spectroscopic, calorimetric and computational methods to explore the binding of the three side-chained triazatruxene derivative, termed azatrux, to a human telomeric G-quadruplex sequence, under conditions of molecular crowding. The binding of azatrux to the tetramolecular parallel [d(TGGGGT)]4 quadruplex in the presence and absence of crowding conditions, was also characterized. The data indicate that azatrux binds in an end-stacking mode to the parallel G-quadruplex scaffold and highlights the key structural elements involved in the binding. The selectivity of azatrux for the human telomeric G-quadruplex relative to another biologically relevant G-quadruplex (c-Kit87up) and to duplex DNA was also investigated under molecular crowding conditions, showing that azatrux has good selectivity for the human telomeric G-quadruplex over the other investigated DNA structures.

► Binding properties of human telomeric quadruplex under molecular crowding. ► Three side-chained triazatruxene derivative azatrux as G-quadruplex ligand. ► Azatrux binds in an end-stacking mode to the parallel G-quadruplex scaffold. ► Azatrux lateral side-chains play a key role in optimizing the binding. ► Azatrux has good selectivity for the human telomeric G-quadruplex over DNA duplex.