2. Academic Validation
  3. New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design

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

  • Eur J Med Chem. 2015 May 5:95:136-52. doi: 10.1016/j.ejmech.2015.03.042.
Exequiel E Barrera Guisasola 1,  Sebastián A Andujar 1,  Ellen Hubin 2,  Kerensa Broersen 3,  Ivonne M Kraan 3,  Luciana Méndez 4,  Carina M L Delpiccolo 4,  Marcelo F Masman 5,  Ana M Rodríguez 1,  Ricardo D Enriz 6
Affiliations

Affiliations

  • 1 Departamento de Química, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina.
  • 2 Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands; Structural Biology Brussels, Department of Biotechnology (DBIT), Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussels, Belgium; VIB Department of Structural Biology, Pleinlaan 2, B-1050 Brussels, Belgium.
  • 3 Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands.
  • 4 Instituto de Química Rosario (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
  • 5 Department of Molecular Dynamics, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
  • 6 Departamento de Química, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina. Electronic address: denriz@unsl.edu.ar.
PMID: 25805447 DOI: 10.1016/j.ejmech.2015.03.042
Abstract

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.

Keywords

Aggregation modulating effect; Amyloid β-protein; Mimetic peptides; Molecular dynamics simulations; Molecular modelling.

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