New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design

A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence an...

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Bibliographic Details
Published in:	European journal of medicinal chemistry Vol. 95; pp. 136 - 152
Main Authors:	Barrera Guisasola, Exequiel E., Andujar, Sebastián A., Hubin, Ellen, Broersen, Kerensa, Kraan, Ivonne M., Méndez, Luciana, Delpiccolo, Carina M.L., Masman, Marcelo F., Rodríguez, Ana M., Enriz, Ricardo D.
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 05-05-2015
Subjects:	Aggregation modulating effect Alzheimer Disease - drug therapy Amyloid beta-Peptides - chemistry Amyloid β-protein Drug Design Humans Hydrophobic and Hydrophilic Interactions Mimetic peptides Models, Molecular Molecular Dynamics Simulation Molecular dynamics simulations Molecular modelling Peptide Fragments - pharmacology Peptidomimetics - chemistry Peptidomimetics - pharmacology Protein Conformation Water Molecular modelling Mimetic peptides Molecular dynamics simulations Amyloid β-protein Aggregation modulating effect
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Summary:	A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compounds were obtained based on a molecular modelling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and transmission electron microscopy revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compounds. Dot blot analysis suggested a decrease of soluble oligomers strongly associated with cognitive decline in Alzheimer's disease. For the molecular dynamics simulations, we used an Aβ42 pentameric model where the compounds were docked using a blind docking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamics simulations were carried out in explicit water. We also measured parameters or descriptors that allowed us to quantify the effect of these compounds as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of our Aβ42 protofibril model were identified. Among others we observed the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. Our results may be helpful in the structural identification and understanding of the minimum structural requirements for these molecules and might provide a guide in the design of new aggregation modulating ligands. [Display omitted] •A new series of mimetic peptides with relevant Aβ aggregation modulating effect is reported.•These compounds were obtained based on a molecular modelling study.•The dynamic behavior of the complexes was analyzed using extensive MD simulations.•Aggregation modulating activities were measured using different biophysical assays.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2015.03.042