October 25, 2019

Garcinol and Related Polyisoprenylated Benzophenones as Topoisomerase II Inhibitors: Biochemical and Molecular Modeling Studies

Journal of Natural Products Volume 82, Issue 10, 25 October 2019, Pages 2768-2779

Garcinol, a polyisoprenylated benzophenone isolated from Garcinia genus, has been reported to inhibit eukaryotic topoisomerase I and topoisomerase II at concentrations comparable to that of etoposide (∼25−100 μM). With the aim to clarify the underlying molecular mechanisms by which garcinol inhibits human topoisomerase IIα and topoisomerase IIβ, biochemical assays along with molecular docking and molecular dynamics studies were carried out on garcinol and six congeners. The biochemical results revealed that garcinol derivatives appear to act as catalytic inhibitors of topoisomerase II and to inhibit ATP hydrolysis by topoisomerase II via some form of mixed inhibition. The computational investigation identified the structural elements responsible for binding to the biological target and also provided information for the eventual design of more selective and potent analogues. Collectively, our data suggest that garcinol-type agents may bind to the DNA binding surface and/or ATP domain of type II topoisomerases to antagonize function.

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Other Autors

Milena Masullo
Afif F. Bandak
James M. Berger
Raffaele Riccio
Sonia Piacente
Giuseppe Bifulco