Computational selection of inhibitors of Aβ aggregation and neuronal toxicity

Abstract

Alzheimer’s Disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-β protein (Aβ). Disease symptoms can be alleviated, in vitro and in vivo, by “β-sheet breaker” pentapeptides that reduce plaque volume. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related β-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Aβ. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features in a conformation similar to the active peptides were selected, ranked by docking solubility parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Aβ aggregation at 2–3 μM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Aβ on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD.

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

“…However, structural studies of oligomers and the conformational transitions taking place during the aggregation process are limited by the size range and transitory nature of these aggregates [28]. Elucidation of the mechanisms driving the aggregation, including structural transitions in the peptide, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates [29]. Our group already demonstrated that oligomers and fibrils of Ab(1-42) do not share the same b-sheet organization.…”

Identification of Novel Short Peptide Inhibitors of Soluble 37/48 kDa Oligomers of Amyloid β42

“…Small molecules can be selected by the computational method, as described by Chen et al 10) A synthetic study of peptide mimics and drug design is under planning in our laboratory.…”

“…Determining the minimum length of peptides for inhibition of the soluble oligomerization of A42 is also necessary to design small molecules or peptide mimics that can act within brain cells. 10) Phage display is a rapid, potent method of obtaining novel, essential sequences from random libraries for binding to target molecules. 11,12) In this study, we prepared 3-and 4-residue random peptide libraries and screened for peptides capable of inhibition of soluble oligomerization of A42 by phage display.…”

New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design

“…Chen et al reported small mimetic peptides with similar ability to inhibit and reverse Ab misfolding and aggregation, but with potentially better drug-like properties [31]. Among these molecules, BSBM6 (1) (Fig.…”