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

EXEQUIEL E. BARRERA GUISASOLA; SEBASTIÁN A. ANDUJAR; ELLEN HUBIN; KERENSA BROERSEN; IVONNE M. KRAAN; LUCIANA MÉNDEZ; CARINA M.L. DELPICCOLO; MARCELO F. MASMAN; ANA M. RODRÍGUEZ; RICARDO D. ENRIZ

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Lugar: Paris; Año: 2015 vol. 95 p. 136 - 152

0223-5234

A new series of mimetic peptides possessing a significant Ab 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 Ab 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 Ab42 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 Ab aggregation. Thus, significant alterations in the structure of our Ab42 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 b1 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.