Computational Modeling Core Facility, Institute for Applied Life Sciences (IALS) , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
Department of Biochemistry and Molecular Biology , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
J Chem Theory Comput. 2019 Oct 8;15(10):5169-5174. doi: 10.1021/acs.jctc.9b00599. Epub 2019 Sep 4.
Aggregation of amyloid-β (Aβ) peptides is a crucial step in the progression of Alzheimer's disease (AD). Identifying aggregation inhibitors against AD has been a great challenge. We report an atomistic simulation study of the inhibition mechanism of two small molecules, homotaurine and -inositol, which are AD drug candidates currently under investigation. We show that both small molecules promote a conformational change of the Aβ42 monomer toward a more collapsed phase through a nonspecific binding mechanism. This finding provides atomistic-level insights into designing potential drug candidates for future AD treatments.
淀粉样蛋白-β (Aβ) 肽的聚集是阿尔茨海默病 (AD) 进展的关键步骤。鉴定针对 AD 的聚集抑制剂一直是一个巨大的挑战。我们报告了两种小分子，即同型牛磺酸和肌醇，的抑制机制的原子模拟研究，它们是目前正在研究的 AD 药物候选物。我们表明，这两种小分子通过非特异性结合机制促进 Aβ42 单体向更折叠的相的构象变化。这一发现为设计未来 AD 治疗的潜在药物候选物提供了原子水平的见解。
