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

To revert amyloid fibrils back to native state is a challenge in finding solution to prevent neurodegenerative diseases. We have adopted a structure-property-energetics correlation based 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 quantitative comprehensive biophysical approach in identifying functionality in the molecules which offers this property in terms of polarity and hydrogen bonding. Our objective to identify functionality on drug which 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, F19-NMR chemical shifts, hydrodynamic diameters and thermal expansion coefficients to demonstrate that the open chain molecule is a better inhibitor in fibrillation but its efficiency decreases with the formation of amorphous aggregates, as compared to the molecule having uracil ring. The results have provided quantitative insights into role of polarity and hydrogen bonding in prevention of the fibrillation process. The approach adopted here highlights physical chemistry underlying such biologically important processes and hence have significance in deriving guidelines for rational drug design.