Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.
De Simone, Alfonso
The Journal of Chemical Physics
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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
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.
Amino Acid Sequence, Amyloid beta-Peptides, Binding Sites, Drug Design, Molecular Dynamics Simulation, Molecular Sequence Data, Peptide Fragments, Protein Binding, Protein Structure, Secondary, Solubility
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.
Wellcome Trust (089703/Z/09/Z)
External DOI: https://doi.org/10.1063/1.4811831
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263297