Small-Molecule Targeted A Beta(42) Aggregate Degradation: Negatively Charged Small Molecules Are More Promising Than The Neutral Ones

Heavy evidence has confirmed that A beta 42 oligomers are the most neurotoxic aggregates and play a critical role in the occurrence and development of Alzheimer's disease by causing functional neuron death, cognitive damage, and dementia. Disordered A beta 42 oligomers are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, a negatively charged molecule (ER), rather than the neutral TS1 one, is identified by a molecular dynamics simulation method to be more capable of binding and sequestering the intrinsically disordered amyloid-beta peptide A beta 42 in its soluble pentameric state as well as its monomeric components. Results reveal that the ERs interact with A beta and inhibit the primary nucleation pathways in its aggregation process in entropic expansion mechanism for both A beta 42 and A beta 40 oligomers but with opposite characteristics of hydrophobic surface area (HSA). The interaction between A beta 42 oligomer and either charged ER or neutral TS1/TS0 characterizes decreased HSA, and the decrease in ER-involved case is highly visible, consistent with the observations from in silico and in vitro studies. By contrast, the presence of these inhibitors causes the HSA of A beta 40 oligomer to change undetectably and there is even a bit of increase in the histidine isomerized A beta 40 oligomer. The HSA distinction between A beta 42 and A beta 40 oligomer is possibly derived from the different effects of M35-inhibitor interaction, which is analogous to the effect of M35 oxidation. In comparison with the neutral TS1/TS0 inhibitors, ER is more prone to bind the residues located in the central (beta 1) and C-terminal (beta 2) regions of A beta 42 peptide, two key nucleation regions for A beta intramolecular folding, intermolecular aggregation, and assembly. Notably, ER can strongly bind the charged residues, such as K16, K28, D23, to greatly disturb the potential stabilizer (e.g., salt-bridge, etc.) in metastable A beta 42 oligomers and protofibrils. These results illustrate the strategy of overcoming Alzheimer's disease from inhibiting its early stage A beta aggregation with two kinds of small molecules to alter their behavior for therapeutic purposes and strongly recommend paying more attention to the engineering and development of negatively charged inhibitors, the long-term underappreciated ones, targeting the early stage A beta aggregates.