Exploring the Interactions of the Dietary Plant Flavonoids Fisetin and Naringenin with G-Quadruplex and Duplex DNA, Showing Contrasting Binding Behavior: Spectroscopic and Molecular Modeling Approaches

Abstract

Guanine-rich sequences have the propensity to fold into a fourstranded DNA structure known as a G-quadruplex (G4). G4 forming sequences are abundant in the promoter region of several oncogenes and become a key target for anticancer drug binding. Here we have studied the interactions of two structurally similar dietary plant flavonoids fisetin and naringenin with G4 as well as double stranded (duplex) DNA by using different spectroscopic and modeling techniques. Our study demonstrates the differential binding ability of the two flavonoids with G4 and duplex DNA. Fisetin more strongly interacts with parallel G4 structure than duplex DNA, whereas naringenin shows stronger binding affinity to duplex rather than G4 DNA. Molecular docking results also corroborate our spectroscopic results, and it was found that both of the ligands are stacked externally in the G4 DNA structure. C-ring planarity of the flavonoid structure appears to be a crucial factor for preferential G4 DNA recognition of flavonoids. The goal of this study is to explore the critical effects of small differences in the structure of closely similar chemical classes of such small molecules (flavonoids) which lead to the contrasting binding properties with the two different forms of DNA. The resulting insights may be expected to facilitate the designing of the highly selective G4 DNA binders based on flavonoid scaffolds.

Screening the binding potential of quercetin with parallel, antiparallel and mixed G-quadruplexes of human telomere and cancer protooncogenes using molecular docking approach

“…The melting temperature (T m ) was evaluated by a curve fitting procedure as described previously [48,49]. The binding parameters are given in Table 1 These results are consistent with the previously published reports on the stabilization of telomeric G-quadruplex on the quercetin binding [58,59]. Next, we recorded the data with HTPu G4 in the buffer containing 100 mM KCl and 40 wt% PEG 200 in the absence and presence of quercetin with similar ratios.…”

“…Accordingly, specific intermolecular hydrogen bonding between the quercetin and G4, as well as the stacking interactions of aromatic rings may contribute this enthalpic stabilization of G4. These enthalpic stabilization effects on G4 derived from specific interactions have been reported for small molecular ligands effects G4s [50,[56][57][58][59][60][61][62][63][64].…”

Preferential targeting cancer-related i-motif DNAs by the plant flavonol fisetin for theranostics applications

“…The observed enhanced tautomer emission indicated that in the presence of VEGF IM, the Fis molecules experience relatively hydrophobic environments where the external hydrogen bonding interference to ESIPT is minimised, and the ESIPT process is facilitated. The ratio of the intensities of the tautomer (I T ; 535 nm) and the normal band (I N ; 450 nm) emissions (I T /I N ), which is a useful parameter to quantitatively understand the microenvironment of Fis 19,[28][29][30][31] , was approximately 4.8 for 30 μM VEGF IM. The fluorescence spectra of Fis in the presence of c-MYC IM and h-TELO IM are shown in Fig.…”

“…Fis has a remarkable spectroscopic attribute of an exquisitely sensitive intrinsic 'two colour' fluorescence, which arises due to a photoinduced excited state intramolecular proton transfer (ESIPT) reaction (Scheme 1) 17,18 . Previously, our group also explored the preferential interaction of Fis towards G-quadruplex DNA structure 19 . We have also screened various other plant flavonoid molecules such Quercetin, Naringenin, Kaempferol, Morin etc.…”

“…We have also screened various other plant flavonoid molecules such Quercetin, Naringenin, Kaempferol, Morin etc. towards different non-canonical DNA structures such as G-quadruplex and i-motif [19][20][21] . The gathered experiences over the years working with these classes of small molecules and the multi-functional therapeutic activities of Fis along with the very sensitive fluorescence spectroscopic property inspired us to study its interaction with different and biologically important DNA i-motifs.…”