Discovery of New DNA Topoisomerase II Inhibitors using Structure Based Virtual Screening Method

DNA topoisomerases are proved therapeutic targets of anticancer and antibacterial drugs. Structures of topoisomerase–DNA and inhibitor ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. There are two isoforms of Human Topoisomerase II; α and β. Both of them perform similar functions and their levels differ depending on the replicative activity and type of tissue. Topo IIα is preferentially expressed in proliferating cells. Thus selective Topo IIα inhibitors have been of particular interest in cancer therapy, as they may represent a more targeted approach to highly proliferative cells. In this study, we use structure based virtual screening method with molecules which are commercially available in the ZINC database. Docking studies were performed by Glide module available in Schrodinger software, Ligand filtration was also done to obtain an efficient collection of hit molecules by employing Lipinski “rule of five” and pharmacokinetic properties of the compounds were tested using Qikprop module. From approximately ten thousand compounds from Zinc database it was possible to select 4 top chemical structures with good inhibiting profile for topo II, with suitable ADME/Tox properties, thus comp. 1-4 could be the promising inhibitors of human topo IIα enzyme.