Investigation of Isoindolo[2,1-a] quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods

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Abstract

Background: Isoindolo[2,1-alpha] quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning.Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-alpha] quinoxalin-6-imines, by comparing them with known inhibitors.Methods: Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked.Conclusion: Our docking studies performed on Isoindolo[2,1-alpha] quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.
Original languageEnglish
Pages (from-to)208-221
Number of pages14
JournalCurrent Computer-Aided Drug Design
Volume13
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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