Characterization of the Binding Properties of Sorafenib to c-MYC G-Quadruplexes: Evidence for Screening Potential Ligands

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 Gquadruplexes (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.

Exploring the binding effects and inhibiting mechanism of hyperoside to lipase using multi-spectroscopic approaches, isothermal titration calorimetry, inhibition kinetics and molecular dynamics

“…An initial simulation period was discarded as the equilibration time. The contribution of each interaction energy term to the binding process can be calculated by the following formula: 34,35 Δ E = Δ E vdw + Δ E elec + Δ E inter Δ E inter = Δ E bond + Δ E angle + Δ E dihedral + Δ E planarity where Δ E vdw , Δ E elec , Δ E inter represent the vdW, intermolecular electrostatic, and internal energy terms, respectively. Δ E represents the total system energy.…”

“…An initial simulation period was discarded as the equilibration time. The contribution of each interaction energy term to the binding process can be calculated by the following formula: 34,35…”

Interaction Mechanism between α-Lactalbumin and Caffeic Acid: A Multispectroscopic and Molecular Docking Study

“…Molecular Docking of CA on ALA. Computational docking is widely used to study protein−ligand interactions, particularly in drug discovery and development. 45 As shown in Figure 8, CA is docked within the ALA binding site with a minimum binding energy of −4.7 kcal/m. As a result, CA becomes stable in the protein's active site, as shown in Figure 8A.…”

Molecular Recognition Study toward the Mitochondrial Electron Transport Chain Inhibitor Mubritinib and Human Serum Albumin

“…In order to determine K sv , the Stern–Volmer plots ( F 0 / F × [MUB]) have been constructed and the data have been linear fitted to the equation: F 0 F = 1 + K normals normalv [ M U B ] where F and F 0 are the fluorescence intensity at the maximum emission wavelength in the presence and absence of MUB respectively, [MUB] is the equilibrium concentration of MUB, and K sv is the Stern–Volmer constant. , Additionally, the molecular quenching constant k normalq = K normals normalv τ 0 has been calculated from the free biomolecule average lifetime τ 0 = 10 –8 s and the determined K sv . In order to determine the number of binding sites ( n ) and binding constant ( K b ), the double logarithmic transformation was performed and the data were fitted to the equation normall normalo normalg ( F 0 − F F ) = normall normalo normalg .25em K normalb + n × normall normalo normalg .25em [ M U B ] The MUB equilibrium concentration is related to the initial concentration [MUB] 0 and the complex concentration [MUB–HSA] by [MUB] = [MUB] 0 – [MUB–HSA].…”