Ghosh Ritutama, Kishore Nand
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India.
J Phys Chem B. 2020 Oct 15;124(41):8989-9008. doi: 10.1021/acs.jpcb.0c06167. Epub 2020 Oct 5.
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.
将淀粉样蛋白原纤维恢复到其天然状态是寻找预防神经退行性疾病解决方案的一项挑战。我们采用了一种基于结构-性质-能量学相关性的方法，使用具有多个氢键供体和受体的药物（5-氟尿嘧啶和羟基脲）作为抑制剂，针对牛血清白蛋白纤维化的不同阶段。我们在此提出一种定量综合生物物理方法，用于识别分子中的功能，该方法在极性和氢键方面具有此特性。我们通过量热、光谱、体积和微观相关性相结合的方法，实现了识别药物分子上与蛋白质原纤维β链建立有效分子间氢键的功能这一目标。已经在热力学特征、F-NMR化学位移、流体动力学直径和热膨胀系数之间建立了关系，以证明开链分子是更好的纤维化抑制剂，但与具有尿嘧啶环的分子相比，其效率会随着无定形聚集体的形成而降低。这些结果为极性和氢键在预防纤维化过程中的作用提供了定量见解。这里采用的方法突出了此类生物学重要过程背后的物理化学，因此在推导合理药物设计指南方面具有重要意义。
