Identification of small-molecule binding pockets in the soluble monomeric form of the A?42 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 A?42 peptide. We utilised for this purpose a set of structures of the A?42 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 A?42 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 A?42 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.

SUBMITTER: Zhu M 

PROVIDER: S-EPMC5011423 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature