Modulation of Amyloid-β42 Conformation by Small Molecules Through Nonspecific Binding

• DOI: 10.1021/acs.jctc.9b00599
• Publication Date: 2019-09-02T20:39:58Z
• Authors: Chungwen Liang; Sergey N. Savinov; Jasna Fejzo; Stephen J. Eyles; Jianhan Chen
• Keywords: Small Molecule Libraries; 0301 basic medicine; Protein Aggregates; 03 medical and health sciences; Amyloid beta-Peptides; Binding Sites; Protein Conformation; Humans; Molecular Dynamics Simulation; Protein Binding

Aggregation of amyloid-β (Aβ) peptides is a crucial step in the progression of Alzheimer's disease (AD). Identifying aggregation inhibitors against AD has been a great challenge. We report an atomistic simulation study of the inhibition mechanism of two small molecules, homotaurine and scyllo-inositol, which are AD drug candidates currently under investigation. We show that both small molecules promote a conformational change of the Aβ42 monomer toward a more collapsed phase through a nonspecific binding mechanism. This finding provides atomistic-level insights into designing potential drug candidates for future AD treatments.