Searching for improved mimetic peptides inhibitors preventing conformational transition of amyloid-β42 monomer

[Display omitted] •A novel mimetic peptide that inhibits Aβ cytotoxicity at submicromolar concentration is reported.•Antiaggregant activities were measured using different biophysical assays.•Complex formation and its dynamic behaviour was analysed using docking and enhanced sampling MD.•Docking posits compound 7 interacts with the CHC region implicated in Aβ oligomerization.•The mimetic peptide would act through the inhibition of the conformational transition of Aβ42. A series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early “on-pathway” events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer’s disease.