Structural Reorganization Mechanism of the Aβ Fibril Mediated by -Substituted Oligopyrrolamide ADH-353.

The inhibition of amyloid-β (Aβ) fibrillation and clearance of Aβ aggregates have emerged as a potential pharmacological strategy to alleviate Aβ aggregate-induced neurotoxicity in Alzheimer's disease (AD). Maity et al. shortlisted ADH-353 from a small library of positively charged -substituted oligopyrrolamides for its notable ability to inhibit Aβ fibrillation, disintegrate intracellular cytotoxic Aβ oligomers, and alleviate Aβ-induced cytotoxicity in the SH-SY5Y and N2a cells. However, the molecular mechanism through which ADH-353 interacts with the Aβ fibrils, leading to their disruption and subsequent clearance, remains unclear. Thus, a detailed molecular mechanism underlying the disruption of neurotoxic Aβ fibrils (PDB ID 2NAO) by ADH-353 has been illuminated in this work using molecular dynamics simulations. Interestingly, conformational snapshots during simulation depicted the shortening and disappearance of β-strands and the emergence of a helix conformation, indicating a loss of the well-organized β-sheet-rich structure of the disease-relevant Aβ fibril on the incorporation of ADH-353. ADH-353 binds strongly to the Aβ fibril (Δ= -142.91 ± 1.61 kcal/mol) with a notable contribution from the electrostatic interactions between positively charged -propylamine side chains of ADH-353 with the glutamic (Glu3, Glu11, and Glu22) and aspartic (Asp7 and Asp23) acid residues of the Aβ fibril. This aligns well with heteronuclear single quantum coherence NMR studies, which depict that the binding of ADH-353 with the Aβ peptide is driven by electrostatic and hydrophobic contacts. Furthermore, a noteworthy decrease in the binding affinity of Aβ fibril chains on the incorporation of ADH-353 indicates the weakening of interchain interactions leading to the disruption of the double-horseshoe conformation of the Aβ fibril. The illumination of key interactions responsible for the destabilization of the Aβ fibril by ADH-353 in this work will greatly aid in designing new chemical scaffolds with enhanced efficacy for the clearance of Aβ aggregates in AD.