title: New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design.
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.
authors: Departamento de Química, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina.
authors: Exequiel E
authors: EE
authors: Barrera Guisasola
authors: Departamento de Química, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina.
authors: Sebastián A
authors: SA
authors: Andujar
authors: 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.
authors: Ellen
authors: E
authors: Hubin
authors: Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands.
authors: Kerensa
authors: K
authors: Broersen
authors: Nanobiophysics Group, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands.
authors: Ivonne M
authors: IM
authors: Kraan
authors: Instituto de Química Rosario (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
authors: Luciana
authors: L
authors: Méndez
authors: Instituto de Química Rosario (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
authors: Carina M L
authors: CM
authors: Delpiccolo
authors: Department of Molecular Dynamics, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors: Marcelo F
authors: MF
authors: Masman
authors: Departamento de Química, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina.
authors: Ana M
authors: AM
authors: Rodríguez
authors: 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.
authors: Ricardo D
authors: RD
authors: Enriz
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D014867:Water
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D057786:Peptidomimetics; D014867:Water
keywords: Aggregation modulating effect; Amyloid β-protein; Mimetic peptides; Molecular dynamics simulations; Molecular modelling