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

Abstract

The bioinformatics analysis revealed that more than 400,000 DNA sequences within the human genome have the potential of forming G-quadruplex structures. Specifically, G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, transcription and translation of cancer-related genes and hence a therapeutic target. Targeting G4 with small molecules may regulate its expression. Chemical molecules generally shows more cellular toxicity while natural small molecules are more bioavailable and hence shows high biological activity together with low toxicity. In the present study, we have screened the binding potential of quercetin with parallel, anti-parallel and mixed conformations of telomeric G-quadruplexes, cancer protoncogenes and RNA G-quadruplex using molecular docking approach. Our results suggest that the quercetin mainly binds with grooves of all selected G-quadruplxes and its planer aromatic rings stabilizes the structure by π-π stacking. The binding energies were in a range of − 40.24 to − 17.11 kcal/ mol, − 35.73 to − 18.09 kcal/mol, − 32.68 to − 22.47 kcal/mol for telomeric parallel, anti-parallel and mixed G-quadruplexes respectively. Further, binding energies of quercetin with selected cancer proto-oncogenes are in a range of − 38.67 to − 12.95 kcal/mol and − 14.8 and − 14.6 kcal/mol for selected RNA G-quadruplex. Hence, this study highlights the comparative differences in binding energies of quercetin even with a group of single conformation of G-quadruplex and helpful to evaluate the binding potential of quercetin to inhibit the activity of telomerases and down-regulate the expression of oncogenes and to be used as a potential anti-cancer agent.

Discriminating between Parallel, Anti-Parallel and Hybrid G-Quadruplexes: Mechanistic Details on Their Binding to Small Molecules

“…The natural alkaloid allocryptopine (Figure 6d) showed a binding mode via groove and/or loop binding to G4s that is distinct from the conventional π-stacking of the ligands on external G-quartets and drove selectivity for antiparallel topologies; in this paper, the binding details and geometries are further inspected using steady-state and time-resolved anisotropy measurements [70]. [68], (c) [69], (d) [70], (e) [71], (f) [72] and (g) [73]. Red letters evidence parallel G4s high selectivity, blue letters correspond to molecules selective for antiparallel topology, and the systems with other/mixed behaviour have black lettering.…”

“…A coumarin-benzothiazole hybrid (Figure 6a) was recently found to exhibit enhanced fluorescence emission upon sitting-atop binding to a parallel G4 topology, with no response for the antiparallel counterpart; this "turn-on" response is used to sense the presence of parallel-form inducers such as K + ions, with excellent selectivity for K + in the presence of other potential metal ion interferences [67]. An interesting work by Saxena and coworkers compares the energies for the binding of the flavonoid quercetin (Figure 6b) with some DNA and RNA G4s: differently from the more abundant sitting-atop binding mode, quercetin interacts in all cases from the G4 groove and is found to produce adducts that are more stabilised in the case of parallel DNA G4, whereas RNA G4 adducts are all less favoured (likely due to less efficient hydrogen bonding) [68]. Berberine-like structures also showed important potentialities.…”

“…Molecular dynamics confirmed the formation of H-bonds and very favourable complementary geometry for lateral/groove binding, but the same is not found in sitting atop structures; on the whole, both experiments and calculations show that the two Figure 6. Molecular structures of the selective G4 binders of the pericyclic compounds family reviewed here: (a) [67], (b) [68], (c) [69], (d) [70], (e) [71], (f) [72] and (g) [73]. Red letters evidence parallel G4s high selectivity, blue letters correspond to molecules selective for antiparallel topology, and the systems with other/mixed behaviour have black lettering.…”

“…Figure 6. Molecular structures of the selective G4 binders of the pericyclic compounds family reviewed here: (a)[67], (b)[68], (c)[69], (d)[70], (e)[71], (f)[72] and (g)[73]. Red letters evidence parallel G4s high selectivity, blue letters correspond to molecules selective for antiparallel topology, and the systems with other/mixed behaviour have black lettering.…”

Evaluating Molecular Docking Software for Small Molecule Binding to G-Quadruplex DNA

“…Docking can predict the 3D structures of G4-ligand complexes on a large scale in silico and aid the design of small molecules targeting the G4s [ 16 , 17 , 18 ]. In recent years, docking has also been commonly applied in targeting DNA G4s for hit identification in virtual screening studies or to predict the binding pose of a ligand [ 16 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. For example, in a screening of Pt(II)-Phenanthroline complexes with double-stranded DNA and G-quadruplexes, Ang et al applied AutoDock Vina in combination with biophysical approaches to study the correlations between ligand structure and selectivity for G4 end-stacking over groove-binding [ 24 ].…”