np9b00382_si_001.pdf (2.57 MB)
Garcinol and Related Polyisoprenylated Benzophenones as Topoisomerase II Inhibitors: Biochemical and Molecular Modeling Studies
journal contribution
posted on 2019-10-16, 17:06 authored by Simone Di Micco, Milena Masullo, Afif F. Bandak, James M. Berger, Raffaele Riccio, Sonia Piacente, Giuseppe BifulcoGarcinol, 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.