An <i>in silico</i> investigation of the binding of flavones with CREB1 oncogene G-quadruplex DNA

Stabilizing G-quadruplex structures through small molecule binding is an important area of research in cancer therapy. Cyclic AMP response element-binding protein 1 (CREB1) is a transcription factor of the CREB family that acts as an oncogene. It governs various roles in cellular processes, including the regulation of genes. CREB1 has guanine-rich regions which can form G-quadruplex (GQ) structures. Flavones are natural compounds with anticancer properties. We have investigated the binding mode and interaction mechanisms of three flavone compounds with the CREB1 GQ (CR-GQ) employing molecular docking and 100 ns molecular dynamics simulations, followed by an umbrella sampling method. The binding free energies estimated from MM-PBSA were -47.95, -107.55 and -98.28 kcal/mol, respectively, for flavone, baicalein and chrysin, showing that baicalein and chrysin bind with lower energy than flavone. Root mean square deviations and root mean square fluctuation values indicate that the GQ DNA-ligand system is stable throughout the simulations. The binding free energies and the estimated minimum values in the potential of mean force suggest that the binding reaction is energetically favourable. The compactness of the complexes is evident from the eigenvector map. Hydrogen bonds, pi-pi interactions and van der Waals interactions are the major driving forces in the complex formation. Among the three flavone compounds, baicalein and chrysin complexes are energetically more favourable than the flavone complex. The studied phytochemicals exhibit pharmacokinetic properties, suggesting their potential as promising drug candidates targeting CR-GQ. This study provides pragmatic data for discovering novel drugs targeting CR-GQ and extends the knowledge in stabilizing GQ structures using small molecules.