Investigation of Isoindolo[2,1-a] quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods
2017
Background: Isoindolo[2,1-a]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-a]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-a]quinoxalines and other inhibitors revealed
very important common features responsible for topoisomerase I inhibition that can improve
the design of new inhibitors.
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