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. − …”

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy

“…Drug metabolization and transport are interconnected processes; direct comparison between relevant metabolites of dabrafenib and encorafenib, along with their physical properties and relative contributions to overall drug activity, should be performed in future studies. Dabrafenib binding effects on albumin function in vivo should also be further considered ( 44 ). Other tumor microenvironmental factors, such as acidity, may also affect drug penetration through modulation of protein binding and lipophilicity ( 45 ).…”