A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins

作者：Joshi Priyanka; Chia Sean; Habchi Johnny; Knowles Tuomas P J; Dobson Christopher M; Vendruscolo Michele^*

来源：ACS Combinatorial Science, 2016, 18(3): 144-153.

DOI：10.1021/acscombsci.5b00129

• protein aggregation
• drug discovery
• Alzheimer's disease
• Parkinson's disease

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, A beta, tau, and alpha-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.

• 出版日期2016-3