title: Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.
abstract: The aggregation of intrinsically disordered peptides and proteins is associated with a wide range of highly debilitating neurological and systemic disorders. In this work we explored the potential of a structure-based drug discovery procedure to target one such system, the soluble monomeric form of the Aβ42 peptide. We utilised for this purpose a set of structures of the Aβ42 peptide selected from clusters of conformations within an ensemble generated by molecular dynamics simulations. Using these structures we carried out fragment mapping calculations to identify binding "hot spots" on the monomeric form of the Aβ42 peptide. This procedure provided a set of hot spots with ligand efficiencies comparable to those observed for structured proteins, and clustered into binding pockets. Such binding pockets exhibited a propensity to bind small molecules known to interact with the Aβ42 peptide. Taken together these results provide an initial indication that fragment-based drug discovery may represent a potential therapeutic strategy for diseases associated with the aggregation of intrinsically disordered proteins.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Zhu
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.forename: Gergely
authors.initials: G
authors.lastname: Toth
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)