Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.
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Publication Date
2013-07-21Journal Title
The Journal of Chemical Physics
ISSN
0021-9606
Publisher
AIP
Volume
139
Issue
3
Pages
035101-1-035101-10
Language
English
Type
Article
This Version
AM
Metadata
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Zhu, M., De Simone, A., Schenk, D., Toth, G., Dobson, C., & Vendruscolo, M. (2013). Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.. The Journal of Chemical Physics, 139 (3), 035101-1-035101-10. https://doi.org/10.1063/1.4811831
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.
Keywords
Amino Acid Sequence, Amyloid beta-Peptides, Binding Sites, Drug Design, Molecular Dynamics Simulation, Molecular Sequence Data, Peptide Fragments, Protein Binding, Protein Structure, Secondary, Solubility
Sponsorship
This work was supported by grants from Alzheimer’s Research UK (M.Z.) and the Biotechnology and Biological Sciences Research Council (BBSRC) (C.M.D. and M.V.). We are grateful to Tobin Sosnick and his group for providing the SCM structures of the Aβ42 peptide.
Funder references
MRC (MC_G1000734)
Wellcome Trust (089703/Z/09/Z)
BBSRC (BB/H003843/1)
Identifiers
External DOI: https://doi.org/10.1063/1.4811831
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263297
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