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

Abstract

DNA topoisomerases are proved therapeutic targets of antibacterial and anticancer drugs.Structures of topoisomerase–DNA and inhibitor ternary complexes have revealed the exact bindingsites and mechanisms of topoisomerase poisons. There are two isoforms of Human TopoisomeraseII; α and β. Both of them perform similar functions and their levels differ depending on the replicativeactivity and type of tissue. Topo IIα is preferentially expressed in proliferating cells. Thus, selectiveTopo IIα inhibitors have been of particular interest in cancer therapy, as they may represent a moretargeted approach to highly proliferative cells. In this study, we use structure-based virtual screeningmethod with molecules which are commercially available in the ZINC database. Docking studies wereperformed by Glide module available in Schrödinger software, to obtain an efficient collection of hitmolecules ligand filtration was also done by employing Lipinski’s “rule of five” and pharmacokineticproperties were tested using Qikprop module. From approximately ten thousand compounds fromZinc database we selected 4 top chemical structures with suitable ADME/Tox properties and goodinhibiting profile for topo II. Thus compounds 1-4 could be the promising inhibitors of human topoIIα enzyme.