Design and in silico assessment of quinoxaline platinum complexes as ATPase competitive topoisomerase inhibitors

The topoisomerase TOP2 enzyme is reliant on ATP hydrolysis for DNA relegation, when the ATPase domain is competitively inhibited the enzymatic process is halted and at stable DNA lesion results. This leads to increased apoptotic processes. Metal based topoisomerase inhibitors offer a unique perspective due to their greater diversity of molecular geometries, electrostatic charge and valencies compared with organic based inhibitors. To this effect, a range of platinum (II) complexes were designed and assessed in silico for their ability to competitively inhibit the TOP2 ATPase domain. The ligands were derived from the lead compound XK469 with modifications made on the quinoxaline core which was truncated to include different amino acid groups coordinated to a variety of platinum ions and secondary ligands. Binding energies were calculated for the interaction of the ligands and their complexes with the TOP2 ATPase domain and compared to binding energies for XK469 and ATP with the TOP2 ATPase domain. Platinum coordination was found to be beneficial with the majority of complexes demonstrating a higher binding energy with the TOP2 ATPase domain compared with the lead XK469 compound with 3 complexes exhibiting higher binding energy than the target ATP molecule. The results support two design strategies to improve the affinity for XK469 derivatives for the TOP2 ATPase domain, the first being the coordination of large secondary ligands (2,2'‑bipyridine and 1,10-phenanthroline) in close proximity to the aromatic quinoxaline group, and the second being the coordination of smaller ethylenediamine secondary ligand to a hydrophilic terminus.