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

Year 2019, Volume: 6 Issue: 1, 71 - 78, 15.05.2019

Tugba Ertan-bolelli , Kayhan Bolelli

https://doi.org/10.18596/jotcsa.466457

Cited By: 1

Abstract

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 Schrödinger 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.

 

Keywords

anticancer activity, docking, topoisomerase, virtual screening

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