Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, drug repurposing, which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies, is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of United States Food and Drug Administration approved drugs used in the treatment of depression. We investigated the ability of SSRIs fluvoxamine, fluoxetine, paroxetine, sertraline, and escitalopram on Aβ42 aggregation and fibrillogenesis. Remarkably, the aggregation kinetic experiments carried out demonstrate the anti-Aβ42 aggregation activity of SSRIs fluoxetine, paroxetine, and sertraline at all the tested concentrations (1, 10, 50, and 100 μM). Both fluoxetine and paroxetine were identified as the most promising SSRIs, showing 74.8 and 76% inhibition of Aβ42 aggregation at 100 μM. The transmission electron microscopy experiments and dot-blot study also demonstrate the ability of fluoxetine and paroxetine to prevent Aβ42 aggregation and fibrillogenesis, providing further evidence. Investigating the binding interactions of fluoxetine and paroxetine in the Aβ42 oligomer and fibril models derived from the solid-state NMR structure suggests that these SSRIs interact at a region close to the N-terminal (Lys16-Glu22) in the S-shaped cross-β-strand assembly and reduce Aβ42 fibrillogenesis. On the basis of this study, a pharmacophore model is proposed which shows that the minimum structural requirements to design novel Aβ42 aggregation inhibitors include the presence of one ionizable group, one hydrophobic group, two aromatic rings, and two hydrogen bond donor groups. These studies demonstrate that SSRIs have the potential to prevent Aβ42 aggregation by direct binding and could be beneficial to AD patients on SSRIs.
Keywords: Alzheimer’s disease; Selective serotonin reuptake inhibitors; aggregation kinetics; dot-blot; drug repurposing; fluoxetine; molecular docking; paroxetine; pharmacophore modeling; transmission electron microscopy; β-amyloid.