9,10‐Anthraquinone hinders β‐aggregation: How does a small molecule interfere with Aβ‐peptide amyloid fibrillation?

Abstract

Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease. In this pathology, the b-amyloid peptides (Ab) aggregate into oligomers, protofibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of Alzheimer's disease. Several low-molecular-weight compounds able to impair the Ab aggregation process have been recently discovered; yet, a detailed description of their interactions with oligomers and fibrils is hitherto missing. Here, molecular dynamics simulations are used to investigate the influence of two relatively similar tricyclic, planar compounds, that is, 9, 10-anthraquinone (AQ) and anthracene (AC), on the early phase of the aggregation of the Ab heptapeptide segment H 14 QKLVFF 20 , the hydrophobic stretch that promotes the Ab self-assembly. The simulations show that AQ interferes with b-sheet formation more than AC. In particular, AQ intercalates into the b-sheet because polar interactions between the compound and the peptide backbone destabilize the interstrand hydrogen bonds, thereby favoring disorder. The thioflavin T-binding assay indicates that AQ, but not AC, sensibly reduces the amount of aggregated Ab 1-40 peptide. Taken together, the in silico and in vitro results provide evidence that structural perturbations by AQ can remarkably affect ordered oligomerization. Moreover, the simulations shed light at the atomic level on the interactions between AQ and Ab oligomers, providing useful insights for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer's disease.

Disordered Binding of Small Molecules to Aβ(12–28)

“…The A␤(12-28) peptide and inhibitors were modeled using the united atoms CHARMM PARAM19 force field with its default truncation scheme for non-bonded interactions (cut-off of 7.5 Å). Parameters for 1,4-napthoquinon-2-yl-L-tryptophan (NQTrp), anthracene, and 9,10-anthraquinone were derived as reported (37,43). Protonation states of titratable residues were considered at neutral pH.…”

“…Nevertheless, the identification and detailed biophysical characterization of small molecules that modulate A␤ peptide self-assembly are expected to generate new lead candidates for clinical studies. Several therapeutic strategies have been suggested for blocking key steps in the amyloid aggregation proc-ess, including the direct inhibition of aggregation by using either peptides or small molecules (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). As an example, indole derivatives inhibited fibril formation of A␤ peptide (39,40) and lysozyme (41).…”

“…As an example, indole derivatives inhibited fibril formation of A␤ peptide (39,40) and lysozyme (41). Anthraquinones were shown to be inhibitors of Tau protein (42) and A␤40 aggregation (37), and hybrid molecules bearing both indole and quinone rings have been effective in the recovery of a fly model of AD (43). In addition, antioxidants (e.g.…”

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

“…Convertino et al were among the first to use MD simulations in this respect, examining the interactions of 9,10-anthraquinone and anthracene with a fragment of Aβ encompassing the sequence H 14 QKLVFF 20 . 99 Using Aβ 14−20 trimers as a model Aβ aggregate, they determined that 9,10-anthraquinone could compete for backbone hydrogen bonds, resulting in what they authors termed a "butter-knife" mechanism for separating the β-strands. Anthracene, lacking carbonyl moieties, did not exhibit this effect.…”

Flexibility and binding affinity in protein–ligand, protein–protein and multi-component protein interactions: limitations of current computational approaches

“…To increase our knowledge on the exact mechanism of action for known Ab drugs, several modelling studies were conducted [177][178][179][180][181][182]. For instance, all-atom MD/REMD studies looked at the impact of organic molecules, such as naproxen, on Ab dimers [178] and protofilaments [179] or the impact of N-methylated peptide-based inhibitors [180,181] and the Pittsburg compound on Ab protofilaments [182].…”