Morphological inhibitors of aggregation-prone amyloid-β conformers: A computational exploration

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. It is associated with the self-assembly of the amyloid-$\beta$ peptide, a soluble intrinsically disordered protein naturally present in the brain parenchyma in various alloforms. This study presents a computational approach to identify possible modulators of the monomeric aggregation-prone conformations of amyloid-$\beta$, a critical intermediate in the fibrillation process. A structure-based virtual screening campaign was designed using a structural ensemble to identify potential binders. The workflow included binding site identification, small molecule–peptide docking, protein–protein docking, and molecular dynamics simulations to evaluate interaction stability and aggregation propensity. From this pipeline, a set of novel molecules was identified as capable of interacting with aggregation-prone forms of amyloid-$\beta$, potentially reducing their tendency to form toxic aggregates.