Kundaikar Harish S, Degani Mariam S
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Mumbai, 400 019, India.
Chem Biol Drug Des. 2015 Oct;86(4):805-12. doi: 10.1111/cbdd.12555. Epub 2015 Mar 28.
Aggregation of β-amyloid (Aβ) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease (AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand the differences in interactions of known therapeutic agents such as curcumin, fluorescence-based amyloid staining agents such as thioflavin T, and diagnostic agents such as florbetapir (AV45), with Aβ protofibrils. We show that therapeutic agents bind to and distort the protofibrils, thus causing destabilization or prevention of oligomerization, in contrast to diagnostic agents which bind to but do not distort such structures. This has implications in the rational design of ligands, both for diagnostics and therapeutics of AD.
β-淀粉样蛋白（Aβ）聚集成寡聚体并进一步形成纤维被认为是阿尔茨海默病（AD）病理的关键因素。在本研究中，采用图谱绘制和对接来研究配体与原纤维的结合。随后进行分子模拟，以了解姜黄素等已知治疗剂、硫黄素T等基于荧光的淀粉样蛋白染色剂以及氟代硼吡咯（AV45）等诊断剂与Aβ原纤维相互作用的差异。我们发现，与结合但不扭曲此类结构的诊断剂不同，治疗剂会结合并扭曲原纤维，从而导致其不稳定或阻止寡聚化。这对AD诊断和治疗配体的合理设计具有重要意义。
