Physicochemical Insights into the Role of Drug Functionality in Fibrillation Inhibition of Bovine Serum Albumin

Abstract

To revert amyloid fibrils to their native state is a challenge in finding a solution to prevent neurodegenerative diseases. We have adopted a structure−property−energetics correlationbased approach with drugs (5-fluorouracil and hydroxyurea) having multiple hydrogen-bond donors and acceptors as inhibitors targeting different stages of bovine serum albumin fibrillation.We present here a quantitative comprehensive biophysical approach for identifying functionalities in molecules, which offers this feature in terms of polarity and hydrogen bonding. Our objective of identifying the functionality on a drug molecule that establishes effective intermolecular hydrogen bonding with β-strands of protein fibrils was achieved by combined calorimetric, spectroscopic, volumetric, and microscopic correlations. Relationships have been established among thermodynamic signatures, F 19 -NMR chemical shifts, hydrodynamic diameters, and thermal expansion coefficients to demonstrate that the open-chain molecule is a better inhibitor of fibrillation, but its efficiency decreases with the formation of amorphous aggregates, as compared to the molecule having a uracil ring. The results have provided quantitative insights into the role of polarity and hydrogen bonding in prevention of the fibrillation process. The approach adopted here highlights the physical chemistry underlying such biologically important processes and hence has significance in deriving guidelines for rational drug design.

Insight into the Effect of Submicellar Concentrations of Sodium Deoxycholate on the Structure, Stability, and Activity of Bovine and Human Serum Albumin: An Interesting Comparison between Single and Double Tryptophan Proteins

“…In the present study, the effect of NaDC at [NaDC]/[SA] = 100 on the thermal stability of the serum albumins has been analyzed by monitoring changes in the heat capacity as a function of temperature in the DSC thermogram. As Figure indicates, the DSC thermogram of native BSA exhibits an endothermic peak having a melting temperature of ∼56 °C in the aqueous medium, which is in good agreement with the reported values . In the presence of NaDC, the melting temperature of BSA rises to 70 °C, which suggests significant protection by NaDC of BSA against thermal denaturation.…”

Combined theoretical and experimental insights on DNA and BSA binding interactions of Cu(ii) and Ni(ii) complexes along with the DPPH method of antioxidant assay and cytotoxicity studies

“…S8b †). Upon excitation at 295 nm Tryptophan (W) of BSA elicits uorescence emission centered at 350 nm, [43][44][45][46][47] which shows reduction in its intensity (Fig. 5a and b) with successive addition of both the complexes as a result of quenching.…”