Bioassays and In Silico Methods in the Identification of Human DNA Topoisomerase IIα Inhibitors

Author(s): Kaja Bergant , Matej Janezic , Andrej Perdih* .

Journal Name: Current Medicinal Chemistry

Volume 25 , Issue 28 , 2018

  Journal Home
Translate in Chinese


Background: The family of DNA topoisomerases comprises a group of enzymes that catalyse the induction of topological changes to DNA. These enzymes play a role in the cell replication machinery and are, therefore, important targets for anticancer drugs - with human DNA topoisomerase IIα being one of the most prominent. Active compounds targeting this enzyme are classified into two groups with diverse mechanisms of action: DNA poisons act by stabilizing a covalent cleavage complex between DNA and the topoisomerase enzyme, transforming it into a cellular toxin, while the second diverse group of catalytic inhibitors, provides novel inhibition avenues for tackling this enzyme due to frequent occurrence of side effects observed during the DNA poison therapy.

Methods: Based on a comprehensive literature search we present an overview of available bioassays and in silico methods in the identification of human DNA topoisomerase IIα inhibitors.

Results and Conclusion: A comprehensive outline of the available methods and approaches that explore in detail the in vitro mechanistic and functional aspects of the topoisomerase IIα inhibition of both topo IIα inhibitor groups is presented. The utilized in vitro cell-based assays and in vivo studies to further explore the validated topo IIα inhibitors in subsequent preclinical stages of the drug discovery are discussed. The potential of in silico methods in topoisomerase IIα inhibitor discovery is outlined. A list of practical guidelines was compiled to aid new as well experienced researchers in how to optimally approach the design of targeted inhibitors and validation in the preclinical drug development stages.

Keywords: Human DNA topoisomerase IIα, catalytic inhibitors, DNA poisons, anticancer agents, bioassays, medicinal chemistry.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Page: [3286 - 3318]
Pages: 33
DOI: 10.2174/0929867325666180306165725
Price: $58

Article Metrics

PDF: 33
PRC: 1