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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

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Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.

Zhu Maximillian M De Simone Alfonso A Schenk Dale D Toth Gergely G Dobson Christopher M CM Vendruscolo Michele M

The Journal of chemical physics 20130701 3

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 the ...[more]

PMID: 23883055

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Project description:Human mini-brains (MB) are cerebral organoids that recapitulate in part the complexity of the human brain in a unique three-dimensional in vitro model, yielding discrete brain regions reminiscent of the cerebral cortex. Specific proteins linked to neurodegenerative disorders are physiologically expressed in MBs, such as APP-derived amyloids (A?), whose physiological and pathological roles and interactions with other proteins are not well established in humans. Here, we demonstrate that neuroectodermal organoids can be used to study the A? accumulation implicated in Alzheimer's disease (AD). To enhance the process of protein secretion and accumulation, we adopted a chemical strategy of induction to modulate post-translational pathways of APP using an Amyloid-? Forty-Two Inducer named Aftin-5. Secreted, soluble A? fragment concentrations were analyzed in MB-conditioned media. An increase in the A?42 fragment secretion was observed as was an increased A?42/A?40 ratio after drug treatment, which is consistent with the pathological-like phenotypes described in vivo in transgenic animal models and in vitro in induced pluripotent stem cell-derived neural cultures obtained from AD patients. Notably in this context we observe time-dependent A? accumulation, which differs from protein accumulation occurring after treatment. We show that mini-brains obtained from a non-AD control cell line are responsive to chemical compound induction, producing a shift of physiological A? concentrations, suggesting that this model can be used to identify environmental agents that may initiate the cascade of events ultimately leading to sporadic AD. Increases in both A? oligomers and their target, the cellular prion protein (PrPC), support the possibility of using MBs to further understand the pathophysiological role that underlies their interaction in a human model. Finally, the potential application of MBs for modeling age-associated phenotypes and the study of neurological disorders is confirmed.

Dataset Information

Identification of small-molecule binding pockets in the soluble monomeric form of the A?42 peptide.

Publications

Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.

Similar Datasets

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