CONICET | Buscador de Institutos y Recursos Humanos

A new series of mimetic peptides possessing a significant Ab aggregation modulating effect was reportedhere. These compounds were obtained based on a molecular modelling study which allowed us toperform a structural-based virtual selection. Monitoring Ab aggregation by thioflavin T fluorescence andtransmission electron microscopy revealed that fibril formation was significantly decreased upon prolongedincubation in presence of the active compounds. Dot blot analysis suggested a decrease of solubleoligomers strongly associated with cognitive decline in Alzheimer´s disease. For the molecular dynamicssimulations, we used an Ab42 pentameric model where the compounds were docked using a blinddocking technique. To analyze the dynamic behaviour of the complexes, extensive molecular dynamicssimulations were carried out in explicit water. We also measured parameters or descriptors that allowedus to quantify the effect of these compounds as potential inhibitors of Ab aggregation. Thus, significantalterations in the structure of our Ab42 protofibril model were identified. Among others we observed thedestruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizinghydrophobic interaction in the b1 region. Our results may be helpful in the structural identification andunderstanding of the minimum structural requirements for these molecules and might provide a guidein the design of new aggregation modulating ligands.