Inhibitor screening focusing on the oligomerization state of amyloid aggregation

In a complete amyloid aggregation, monomeric peptides/proteins first form soluble oligomers, following by the formation of large pre-fibrillar and mature fibrillar structures. Both amyloid oligomers and fibrils were found to be toxic to human neural cells. Especially, for the cases of Aβ peptides and Tau protein in Alzheimer’s Disease (AD), soluble oligomers are the most toxic aggregated form. Therefore, identifying antagonists of Aβ/Tau oligomerization is a promising strategy in AD drug discovery. Traditional inhibitor screenings for amyloid aggregation have only focused on ligand-amyloid monomers/fibrils affinity and/or fibrillar formation, but not on the oligomerization process as it is a grant challenge to rational design inhibitors of a cellular process. In a recent work, we developed a novel virtual screening (VS) protocol for identification small molecules interfere with the amyloid oligomerization process. The hierarchical VS consisted of docking a ligand to representative oligomers and subsequently performing large-scale atomistic simulations to quantitatively investigate the ability of the ligand in interfering with amyloid oligomerization. We tested the screening protocol using known inhibitors of Aβ and Tau peptides, and the results were consistent with the experimental findings. Thus, we have developed an effective computational protocol to identify the true inhibitors of a cellular process like oligomerization. Additionally, this computational protocol could reveal the molecular mechanism and kinetics of the oligomerization process with/without an inhibitor. A large-scale VS on a subset of ZINC database, which collects commercially-available highly druglike compounds, is ongoing for Tau peptides. We expect to identify a series of inhibitors of Tau oligomerization prior to compound acquisition and Tau-seeding screening.