Introducing Virtual Oligomerization Inhibition to Identify Potent Inhibitors of Abeta Oligomerization.

Amyloid-beta (Abeta) oligomers are known as the most toxic form of Abeta peptides, and they are a major contributor to Alzheimer's disease. Therefore, developing antagonist screening methods for the formation of Abeta oligomers is urgent and of great interest. In this study, we introduce a virtual oligomerization inhibition (VOI), a novel virtual screening protocol which applies atomistic simulation to quantitatively investigate the ability of a ligand in interfering Abeta oligomerization and the formation of Abeta oligomers. Results from the VOI performance on six known inhibitors of Abeta aggregation (brazilin, curcumin, EGCG, ELND005, resveratrol and tacrine) are in excellent agreement with the results of expensive experiments. Moreover, VOI can reveal the mechanism and kinetics of the inhibition process at atomistic level. VOI not only improves the efficiency of the antagonist screening for Abeta oligomerization, but also reduces the cost to perform the task. Attractively, the principle of VOI can also be applied to inhibitor screening for the aggregation of other amyloid proteins/peptides.