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J Chem Theory Comput. 2019 Sep 4. doi: 10.1021/acs.jctc.9b00599. [Epub ahead of print]

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

Author information

1
Computational Modeling Core Facility, Institute for Applied Life Sciences (IALS) , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
2
Department of Biochemistry and Molecular Biology , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
3
Biomolecular NMR Core Facility, Institute for Applied Life Sciences (IALS) , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
4
Mass Spectrometry Core Facility, Institute for Applied Life Sciences (IALS) , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.
5
Department of Chemistry , University of Massachusetts Amherst , Amherst , Massachusetts 01003 , United States.

Abstract

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.

PMID:
31476124
DOI:
10.1021/acs.jctc.9b00599

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