Abstract
Among the multiple factors that induce Alzheimer’s disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1–42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1–42 pathological aggregation represents a field of research interest. Several Aβ1–42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1–42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1–42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1–42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by extracellular fibrillary deposits and intracellular neurofibrillary tangles [1]
The structure of the random coil (RC) conformation corresponds to the Aβ1–42 conformer obtained at 10 ns through molecular dynamics (MD) simulations of 1ZOQ, which has been reported by our research group [26]
The last conformer corresponded to an Aβ1–42 monomer from the 2BEG structure obtained from the PDB, which has a strand-loop-strand structure similar to what is observed in the mature Aβ1–42 fibrils
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by extracellular fibrillary deposits and intracellular neurofibrillary tangles [1]. The primary component of the AD-associated extracellular deposits is a 4-kD peptide that is commonly known as amyloid-β (Aβ) [2]. The most important peptide contains 42 residues (Aβ1–42) [4]. Aβ1–42 undergoes a conformational change from an α-helix to parallel β-sheets, which are connected by a bent structure encompassing residues 23–29, and the close distance between the side chains of Asp and Lys forms an electrostatic interaction [5]. This curved structure may be rate-limiting in fibril formation [6]. The formation of amyloid fibrils has been shown to be more complex than a linear sequential monomer-to-fibril reaction and consists of several toxic intermediates, including soluble oligomers [7,8], that can bind to hippocampal neurons and induce synaptic plasticity dysfunction [9]
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