Aggregation of amyloid-β (Aβ) peptides from soluble monomers to insoluble amyloid fibrils is one of the crucial steps for promoting Alzheimer's disease (AD). Due to the highly disordered behavior of Aβ peptides, identifying inhibitors as potential drug candidates against AD has been a great challenge for the scientific community in the past few decades. Here, we report a molecular dynamics (MD) simulation study of the inhibitory effect of two small molecules drugs (tramiprosate and scyllo-inositol) which are currently under clinical trials. Using replica exchange MD method which extensively explores the conformational space of Aβ42 monomer under the presence of small molecules, we found that both tramiprosate and scyllo-inositol reduce the β-strand propensity of the C-terminus region (I31-A42) and promote a conformational change of Aβ42 monomer toward a more collapsed phase through a non-specific binding mechanism. These findings provide insights into understanding the inhibitory mechanism of two potential small molecule drugs for future AD treatment.

Structural disruption of the amyloid-β peptide induced by small molecules through nonspecific binding

2019 Fall National Meeting

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