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

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 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 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-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.