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Characterization of the Binding Properties of Sorafenib to c-MYC G-Quadruplexes: Evidence for Screening Potential
1Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu610106, China.
Abstract:
Sorafenib (Sor) is a multitarget kinase inhibitor used clinically to treat hepatocellular carcinoma and renal cancer. In this study, the interaction mechanism of Sor with c-MYC G-quadruplexes (G4) was investigated at the molecular level by computer-aided means and experiments. Molecular docking results predicted the binding of Sor to the groove of G4. Molecular dynamics (MD) simulations were used to evaluate the effect of ligand binding to G4. Ultraviolet (UV), fluorescence spectroscopy, and viscosity experiments showed that the binding site was in the groove. The UV and fluorescence titration results showed that compared with traditional G4 ligands represented by compound meso-tetra (N-methyl-4-pyridyl) porphine (TmPyP4), Sor has a lower affinity for G4. Likewise, results from fluorescence resonance energy transfer (FRET) experiments suggested that Sor could have a limited ability to stabilize G4, but it was not as prominent as that of TmPyP4. Time-resolved fluorescence spectroscopy again supported the results from steady-state fluorescence spectroscopy, indicating that a static quenching mechanism mainly drove the process. Studying the interaction mechanism of Sor and c-MYC may inspire the screening of new, selective c-MYC G4 ligands and provide ideas for the design of drugs with good stability, low toxicity, and specific targeting of G4.
Insights
Sorafenib interacts with c-MYC G-quadruplexes (G4) in the groove, showing lower affinity and limited stabilization compared to traditional ligands. This study informs the design of novel, selective G4-targeting drugs.
Area of Science:
- Molecular biology
- Medicinal chemistry
- Biophysics
Background:
- Sorafenib is a kinase inhibitor used for cancer treatment.
- c-MYC G-quadruplexes (G4) are potential therapeutic targets.
Purpose of the Study:
- Investigate the molecular interaction mechanism between Sorafenib and c-MYC G4.
- Evaluate Sorafenib's binding site, affinity, and G4 stabilization ability.
Main Methods:
- Computer-aided methods: Molecular docking and molecular dynamics (MD) simulations.
- Experimental techniques: UV-Vis spectroscopy, fluorescence spectroscopy, viscosity measurements, and FRET assays.
Main Results:
- Sorafenib binds to the groove of c-MYC G4.
- Sorafenib exhibits lower affinity and less G4 stabilization compared to TmPyP4.
- Static quenching mechanism dominates the interaction.
Conclusions:
- Understanding Sorafenib-c-MYC G4 interaction provides insights for developing new, selective G4 ligands.
- This research may guide the design of stable, low-toxicity drugs targeting G4 structures.
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