Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity

Abstract

Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19 F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19 F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib.

Bioactives Promiscuity of Mucin: Insight from Multi-Spectroscopic, Thermodynamic, and Molecular Dynamic Simulation Analyses

“…Fluorescence spectroscopy is a powerful tool for the study of determining interactions between small molecules and biomacromolecules. As demonstrated in Figure a,b, increasing bioactive concentration markedly decreased the intensity of mucin fluorescence with a bathochromic shift in λ em , indicating the formation of a mucin–bioactive complex and the change in the solvent polarity of tryptophan microenvironment of mucin during the binding interaction. ,,, This is in concordance with far-UV CD results exposed above. The decrease in the K SV of the mucin–bioactive complex with increasing temperature indicates static quenching between mucin and the bioactive molecules as the increase in temperature tends to disfavor the binding interaction (Table ).…”

“…The structural changes detected CD spectrum are in good conformity with MD simulations and also coincided with the molecular docking analysis. 32,36,48,52 Docking analysis with both the mucin sequence (PDB ID: 7PP6 and 6RBF) showed similar modes of interaction viz, electrostatic and ionic interactions are dominant in both systems, whereas hydrophobic interactions were also crucial in the binding process. These findings supported the results from thermodynamic parameter analysis from the temperaturedependent fluorescence study.…”

Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study

“…At the highest drug concentration employed (6 μM), approximately 65% of W214 fluorescence quenching is observed in both cases (see the insets in Figure A,B), supporting the formation of steady-state DAB/HSA and VEM/HSA complexes. Of note, free DAB and VEM solutions do not exhibit fluorescence emission in the 300–450 nm range of wavelength, and other HSA fluorescence quenching data were previously described in the literature after interactions with several tyrosine kinase inhibitors or other drugs reporting no visible shifts/changes in the protein emission maximum. − …”

PEGylation Effects on the Interaction of Sphingomyelin Nanoemulsions with Serum Albumin: A Thermodynamic Investigation

“…This is essentially a surface process involving weaker interactions than regular ligand-BSA binding within protein's documented hydrophobic pockets. [44,48,49] Under such circumstances, stoichiometry represents overall, apparent quantities, instead of local, molecular-mechanistic ones. However the different n values obtained for the functionalized SNs under these circumstances are supported by previous mass spectrometry or gel electrophoresis studies [50][51][52] and are also in accordance with literature data showing that the grafting density and the molecular weight of the covering chains influence the adsorption tendency of the proteins on the functionalized surfaces.…”