Artículo
New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design
Barrera Guisasola, Exequiel Ernesto
; Andujar, Sebastian Antonio
; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; Mendez, Luciana
; Delpiccolo, Carina Maria Lujan
; Masman, Marcelo Fabricio
; Rodríguez, Ana M.; Enriz, Ricardo Daniel
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Fecha de publicación:
05/2015
Editorial:
Elsevier
Revista:
European Journal of Medicinal Chemistry
ISSN:
0009-4374
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Molecular
,
Modelling
,
Mimetic
,
Peptides
,
Amyloid
,
Beta-Rpotein
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Licencia
Identificadores
Colecciones
Articulos(IMIBIO-SL)
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos(IQUIR)
Articulos de INST.DE QUIMICA ROSARIO
Articulos de INST.DE QUIMICA ROSARIO
Citación
Barrera Guisasola, Exequiel Ernesto; Andujar, Sebastian Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; et al.; New mimetic peptides inhibitors of Аb aggregation. Molecular guidance for rational drug design; Elsevier; European Journal of Medicinal Chemistry; 95; 5-2015; 136-152
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