Tuning the ring strain effect in acridine derivatives on binding affinity with G-quadruplex-DNA: A computational and experimental study

Abstract

Search for inhibitors to stabilize the telomeric G-quadruplex in order to deter telomerase activity is an active area of research. Inhibitors play an important role to initiate the tumor cell mortalization process. This work reports for the first time of acridine derivative with four membered ammonium rings at the side chain to surpass the binding ability against BRACO-19 with G-quadruplex-DNA. It is known in the literature that acridine based molecule BRACO-19 can effectively bind with G-quadruplex-DNA. The computational study performed in this study revealed that the binding ability of acridine based molecule can be augmented with subtle variation in the molecular structure of the drug like candidates. Steered molecular dynamics (SMD) performed with the acridine derivatives and G-quadruplex DNA showed the importance of ring strain to the side chain of those ligand molecules. The rupture force analysis, hydrogen bonding interactions and the calculated free energies in MM-PBSA method suggest that ligand 3 is superior than that of BRACO-19. The synthesized ligand 3 and BRACO-19 showed the binding constants obtained from ITC measurements are 4 × 106 mol−1 and 2.6 × 106, which corroborates the computational findings.