Combined spectroscopy methods and molecular simulations for the binding properties of trametinib to human serum albumin

Abstract

Trametinib is a novel anticancer drug for treating metastatic cutaneous melanoma. The present study probed into the binding of trametinib to human serum albumin (HSA) through spectroscopy methods and molecular simulations. Trametinib could quench the fluorescence of HSA through static quenching which could be probed via fluorescence spectroscopy and time-resolved fluorescence. Thermodynamic parameters and docking results indicated that hydrogen bonds and van der Waals forces play crucial roles in this binding process, which exerts almost no effect on the HSA conformation under synchronous fluorescence, three-dimensional fluorescence, circular dichroism spectra, and molecular dynamics simulations. Site marker displacement experiments and molecular docking reveal that trametinib primarily binds to Sudlow site I of HSA. In addition, the trametinib-HSA interaction was hardly influenced by varying amino acid (glutamine, alanine, glycine, and valine) concentrations. This study can provide useful information for the pharmacokinetic properties of trametinib.

Insight of the Interaction between 2,4-thiazolidinedione and Human Serum Albumin: A Spectroscopic, Thermodynamic and Molecular Docking Study

“…Far-UV CD of free HSA exhibited double minima at 208 nm (π →π transition) and 222 (n→π transition), which are characteristics of an α-helix rich protein. It should be noted that the α-helix content reported here was lower than that reported in the x-ray crystal structure of HSA (Pdb Id-1AO6), but agreed well with earlier published results [34,47]. This disagreement was ascribed to instrumental differences and by different structural arrangements in the solid (X-ray diffraction) and aqueous state (CD spectroscopy).…”

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

“…A very similar trend was observed at the other two temperature values investigated (data not shown). We also note that the α-helix contents estimated from our CD data are slightly lower than those derived from available HSA X-ray-derived crystal structures (∼67%), although they are in line with other literature reports. ,,− This discrepancy can be attributed to several factors, including the use of different instruments and experimental conditions, as well as changes in the protein structural element in passing from a solid (X-ray diffraction) to a solution (CD spectroscopy) state.…”

“…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. − …”

Optimization of layering technique and secondary structure analysis during the formulation of nanoparticles containing lysozyme by quality by design approach

“…The spectra were corrected with the PBS buffer background. The α-helix content was calculated by using the following equations [ 29 ]: where [Θ] is molar ellipticity at ca. 208 nm, n is the number of the amino acids, 33000 is the pure -helix content at 208 nm, while 4000 is the amount of the β-sheet and random coil.…”