Expanding the therapeutic arsenal against cancer: a computational investigation of hybrid xanthone derivatives as selective Topoisomerase 2α ATPase inhibitors.

The DNA topoisomerase II (topo II) enzyme plays an important role in the replication, recombination, and repair of DNA. Despite their widespread applications in cancer therapy, new, selective, and potent topo II inhibitors with better pharmaceutical profiles are needed to handle drug resistance and severe adverse effects. In this respect, an array of 36 new anticancer compounds was designed based on a Xanthone core tethered to multifunctional Pyridine-amines and Imidazole scaffold via alkyl chain linkers. An integrated in silico approach was used to understand the structural basis and mechanism of inhibition of the hybrid xanthone derivatives. In this study, we established an initial virtual screening workflow based on pharmacophore mapping, docking, and cancer target association to validate the target selection process. Next, a simulation-based docking was conducted along with pharmacokinetic analysis to filter out the five best compounds ( 7 , 10 , 25 , 27, and 30 ) having binding energies within the range of -60.45 to -40.97 kcal/mol. The screened compounds were further subjected to molecular dynamics simulation for 200 ns followed by MM-GBSA and ligand properties analysis to assess the stability and binding affinity to hTOP2α. The top-ranking hits 3,7-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one ( ligand 7 ) and 3,8-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one ( ligand 25 ) were found to have no toxicity, optimum pharmacokinetic and, DFT properties and stable intermolecular interactions with the active site of hTopo IIα protein. In conclusion, further in vitro and in vivo experimental validation of the identified lead molecules is warranted for the discovery of new human Topoisomerase 2 alpha inhibitors.Communicated by Ramaswamy H. Sarma.