Study on the Binding of Five Plant-Derived Secondary Metabolites to G‑Quadruplexes

TL;DR

This study explores how five plant compounds interact with G-quadruplex DNA structures, which could lead to new cancer therapies.

Contribution

The study identifies brucine and ellagic acid as strong G-quadruplex binders using experimental and computational methods.

Findings

Brucine showed the strongest interaction with both G4 sequences tested.

Ellagic acid had binding efficacy comparable to brucine at the c-Myc G4.

Molecular dynamics simulations revealed ligand binding modes and G4 stability.

Abstract

Chemical targeting
of noncanonical secondary structures of DNA
and RNA has emerged as a promising approach for therapeutic development.
The most promising targets seem to be four-stranded structures in
the G-rich regions of the genome, known as G-quadruplexes (G4s), which
are associated with important regulatory regions including promoters.
In this study, we tested and modeled the binding of five plant-derived
secondary metabolites, known for their antiproliferative activity
in vitro, to two G4s found in the human genome: the first at the c-Myc proto-oncogene and the second at the human telomere
repeat region. Among the tested compounds, brucine exhibited the strongest
interaction with both G4 sequences, while ellagic acid demonstrated
binding efficacy comparable to that of brucine in the c-Myc sequence. Through molecular dynamics simulations and the Markov
state model, we explored the binding modes of these ligands, elucidated
the G4 stability in the bound state, and investigated the fluorescence
quenching effect of thioflavin T (ThT) upon its displacement. The
biological effects of these natural compounds were investigated in
human cell lines, and the interaction with G4s was verified experimentally
using a fluorescence displacement assay and CD spectroscopy. This
study demonstrates the interaction of these natural compounds with
the G4 structures and their implications for therapeutic targeting.

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