A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies
The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is
no longer viewed as just a biophysical strangeness but it is instead being considered as an important
target for the treatment of various human disorders such as cancers or venous thrombosis. In this
scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the
DNA quadruplex [d(TGGGGT)]4, we recently performed a successful structure-based virtual screening
(VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report
the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes,
namely [d(TGGBrGGT)]4 and [d(TGGGGBrT)]4. The novel NMR spectroscopy experiments combined with
molecular modelling studies, allow for a more detailed picture of the interaction between each binder
and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the
above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind
the DNA quadruplex [d(TGGGGT)]4 with higher affinity than distamycin A, to the best of our knowledge,
the most potent groove binder identified thus far.
Visit publication