Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of A?1-42.

ABSTRACT: Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid ? peptide (A?) is considered the most important due to the ability of the 42-amino acid A? peptides (A?1-42) to form oligomers and fibrils, which constitute A? pathological aggregates. For this reason, the development of inhibitors of A?1-42 pathological aggregation represents a field of research interest. Several A?1-42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for A?1-42 in ?-helix (A?-?), random coil (A?-RC) and ?-sheet (A?-?) conformations. Docking studies revealed that compound 5 had a higher affinity for A?-? and A?-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of A?1-42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design A?1-42 aggregation inhibitors. In conclusion, compounds with higher affinity for A?-? and A?-RC prevented the formation of oligomeric species.

SUBMITTER: Hernandez-Rodriguez M 

PROVIDER: S-EPMC4501547 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature