Structural\nReorganization Mechanism of the Aβ<sub>42</sub> Fibril Mediated\nby <i>N</i>‑Substituted\nOligopyrrolamide ADH-353

The\ninhibition of amyloid-β (Aβ) fibrillation\nand clearance\nof Aβ aggregates have emerged as a potential pharmacological\nstrategy to alleviate Aβ aggregate-induced neurotoxicity in\nAlzheimer’s disease (AD). Maity et al. shortlisted ADH-353\nfrom a small library of positively charged <i>N</i>-substituted\noligopyrrolamides for its notable ability to inhibit Aβ fibrillation,\ndisintegrate intracellular cytotoxic Aβ oligomers, and alleviate\nAβ-induced cytotoxicity in the SH-SY5Y and N2a cells. However,\nthe molecular mechanism through which ADH-353 interacts with the Aβ<sub>42</sub> fibrils, leading to their disruption and subsequent clearance,\nremains unclear. Thus, a detailed molecular mechanism underlying the\ndisruption of neurotoxic Aβ<sub>42</sub> fibrils (PDB ID 2NAO) by ADH-353 has\nbeen illuminated in this work using molecular dynamics simulations.\nInterestingly, conformational snapshots during simulation depicted\nthe shortening and disappearance of β-strands and the emergence\nof a helix conformation, indicating a loss of the well-organized β-sheet-rich\nstructure of the disease-relevant Aβ<sub>42</sub> fibril on\nthe incorporation of ADH-353. ADH-353 binds strongly to the Aβ<sub>42</sub> fibril (Δ<i>G</i><sub>binding</sub>= −142.91\n± 1.61 kcal/mol) with a notable contribution from the electrostatic\ninteractions between positively charged <i>N</i>-propylamine\nside chains of ADH-353 with the glutamic (Glu3, Glu11, and Glu22)\nand aspartic (Asp7 and Asp23) acid residues of the Aβ<sub>42</sub> fibril. This aligns well with heteronuclear single quantum coherence\nNMR studies, which depict that the binding of ADH-353 with the Aβ\npeptide is driven by electrostatic and hydrophobic contacts. Furthermore,\na noteworthy decrease in the binding affinity of Aβ<sub>42</sub> fibril chains on the incorporation of ADH-353 indicates the weakening\nof interchain interactions leading to the disruption of the double-horseshoe\nconformation of the Aβ<sub>42</sub> fibril. The illumination\nof key interactions responsible for the destabilization of the Aβ<sub>42</sub> fibril by ADH-353 in this work will greatly aid in designing\nnew chemical scaffolds with enhanced efficacy for the clearance of\nAβ aggregates in AD.