Novel DNA topoisomerase IIα inhibitors from combined ligand- and structure-based virtual screening

PLoS One. 2014 Dec 9;9(12):e114904. doi: 10.1371/journal.pone.0114904. eCollection 2014.

Abstract

DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. One class of topoisomerase inhibitors, "poisons", binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of DNA. This ultimately leads to the accumulation of DNA double strand breaks and cell death. Different types of topoisomerases occur in human cells and several poisons of topoisomerase I and II are widely used clinically. However, their use is compromised by a variety of side effects. Recent studies confirm that the inhibition of the α-isoform of topoisomerase II is responsible for the cytotoxic effect, whereas the inhibition of the β-isoform leads to development of adverse drug reactions. Thus, the discovery of agents selective for topoisomerase IIα is an important strategy for the development of topoisomerase II poisons with improved clinical profiles. Here, we present a computer-aided drug design study leading to the identification of structurally novel topoisomerase IIα poisons. The study combines ligand- and structure-based drug design methods including pharmacophore models, homology modelling, docking, and virtual screening of the National Cancer Institute compound database. From the 8 compounds identified from the computational work, 6 were tested for their capacity to poison topoisomerase II in vitro: 4 showed selective inhibitory activity for the α- over the β-isoform and 3 of these exhibited cytotoxic activity. Thus, our study confirms the applicability of computer-aided methods for the discovery of novel topoisomerase II poisons, and presents compounds which could be investigated further as selective topoisomerase IIα inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry*
  • Antigens, Neoplasm / metabolism
  • DNA Cleavage / drug effects*
  • DNA Topoisomerases, Type II / chemistry*
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Databases, Pharmaceutical*
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation*
  • Protein Conformation*
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Topoisomerase II Inhibitors
  • DNA Topoisomerases, Type II

Grants and funding

MD acknowledges financial assistance from the University of New South Wales, Australia, in providing a PhD scholarship in the form of a University International Postgraduate Award (UIPA), as well as the Translational Cancer Research Network (TCRN) Australia for providing a Postgraduate Research Scholarship Top-up in 2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.