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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