title: A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: Chia
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Johnny
authors.initials: J
authors.lastname: Habchi
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D064267:Intrinsically Disordered Proteins; D066329:Protein Aggregates; D054852:Small Molecule Libraries; D051844:alpha-Synuclein; D016875:tau Proteins
keywords: Alzheimer’s disease; Parkinson’s disease; drug discovery; protein aggregation