Joshi Priyanka, Chia Sean, Habchi Johnny, Knowles Tuomas P J, Dobson Christopher M, Vendruscolo Michele
Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
ACS Comb Sci. 2016 Mar 14;18(3):144-53. doi: 10.1021/acscombsci.5b00129. Epub 2016 Feb 29.
The aggregation process of intrinsically disordered proteins (IDPs) has been associated with a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Currently, however, no drug in clinical use targets IDP aggregation. To facilitate drug discovery programs in this important and challenging area, we describe a fragment-based approach of generating small-molecule libraries that target specific IDPs. The method is based on the use of molecular fragments extracted from compounds reported in the literature to inhibit of the aggregation of IDPs. These fragments are used to screen existing large generic libraries of small molecules to form smaller libraries specific for given IDPs. We illustrate this approach by describing three distinct small-molecule libraries to target, Aβ, tau, and α-synuclein, which are three IDPs implicated in Alzheimer's and Parkinson's diseases. The strategy described here offers novel opportunities for the identification of effective molecular scaffolds for drug discovery for neurodegenerative disorders and to provide insights into the mechanism of small-molecule binding to IDPs.
内在无序蛋白质（IDP）的聚集过程与多种神经退行性疾病相关，包括阿尔茨海默病和帕金森病。然而，目前临床上尚无针对IDP聚集的药物。为推动这一重要且具有挑战性领域的药物研发项目，我们描述了一种基于片段的方法来生成针对特定IDP的小分子文库。该方法基于使用从文献报道的化合物中提取的分子片段来抑制IDP的聚集。这些片段用于筛选现有的大型通用小分子文库，以形成针对特定IDP的较小文库。我们通过描述针对Aβ、tau和α-突触核蛋白的三个不同小分子文库来说明这种方法，这三种IDP与阿尔茨海默病和帕金森病有关。这里描述的策略为识别用于神经退行性疾病药物研发的有效分子支架提供了新机会，并有助于深入了解小分子与IDP结合的机制。
