Binding of quinazolinones to c-KIT G-quadruplex; an interplay between hydrogen bonding and π-π stacking

Abstract

Stabilization of G-quadruplex structures in the c-KIT promoter with the aid of ligands has become an area of great interest in potential cancer therapeutics. Understanding the binding process between ligands and Gquadruplex is essential for a discovery of selective ligands with high binding affinity to G-quadruplex. In the present work, binding mechanisms of 4-quinazolinones to c-KIT G-quadruplex were investigated theoretically by means of molecular dynamics (MD) simulations. To explore the binding affinity of ligands, binding free energy calculations were performed using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We demonstrate that the key interactions in G-quadruplex-ligand complexes are π-π stacking and hydrogen bond interactions. However, neither of these two interactions alone determines the stability of the Gquadruplex-ligand complexes; rather, it is the result of an intricate interplay between the two. To further examine the nature of the binding, a free energy decomposition analysis at residue level was carried out. The results clearly demonstrate the crucial roles of two hot spot residues (DG4 and DG8) for the binding of ligands to c-KIT G-quadruplex, and highlight the importance of the planar aromatic moiety of ligands in G-quadruplex stabilization via π-π stacking interactions. Our study can assist in the design of new derivatives of 4-quinazolinone with high binding affinity for c-KIT G-quadruplex.

A novel fluorescent probe with a pyrazolo[4,3-c]quinoline core selectively recognizes c-MYC promoter G-quadruplexes

“…36,42 Intermolecular hydrogen bonding between the ligand and c-MYC Pu22 G4 further increases the stabilization and hence improves the fluorescence response. 43…”

“…36,42 Intermolecular hydrogen bonding between the ligand and c-MYC Pu22 G4 further increases the stabilization and hence improves the fluorescence response. 43 In our study, compounds with a pyrazolo[4,3-c]quinoline moiety as the common substructure were tested for fluorescence emission by various oligonucleotides. According to the structures and their fluorescence responses to G4s (Table 1 and Fig.…”

Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future Anticancer Therapeutic Applications

“…These structural data prompted multiple virtual and in vitro screenings of small molecules to identify new entities with the ability to stabilize the G4 arrangements occurring at the KIT promoter. A direct correlation between G4 induction/stabilization and a reduction in the overexpression of c-kit has been systematically observed [ 33 , 34 , 35 , 36 ]. However, no compounds have appeared to be highly selective for KIT -related G4s compared to those occurring at other sites, nor do they discriminate among the solved G4 of KIT promoter [ 37 , 38 ].…”

Theoretical insights into the effect of size and substitution patterns of azobenzene derivatives on the DNA G-quadruplex

“…4,5 For example, stabilization of the G-quadruplex within telomeric DNA and oncogene promoter regions can inhibit telomere elongation in cancer cells and oncogene transcription or translation, respectively. [6][7][8][9] Besides the biological applications, G-quadruplex structures can be utilized as interesting building blocks in nanodevices 10 and optomechanical molecular motors 11 as their folding and unfolding can be controlled in the presence of external stimuli such as, light, 12 pH, 13 metal cations 14,15 and small molecules. [16][17][18] Light is a promising external trigger which has multiple advantages including high precision, eco-friendliness, spatiotemporal control and non-invasiveness features.…”