Quinazolinone acrylamides as anti-Alzheimer agents: Unravelling their modulating efficacy on Amyloidogenic peptide assembly at molecular level

Amyloid beta peptide (Aβ) aggregation in the brain represents an initial detrimental episode in the etiology of Alzheimer’s disease (AD). Recently, it has been discovered that inhibiting Aβ neurotoxicity by modulating highly toxic Aβ oligomers (AβOs) is more rewarding than reducing overall amyloid fibril production. In line with this, here we discuss the efficiency of multifunctional quinazolinone and vanillin acrylamide hybrids (QVA1-5) as modulators of aggregation behaviour. ThT assay inferred the dose dependent intensification of Aβ1-42 aggregation by QVA1-5. FE-SEM study disclosed enormously distinctive differences amongst the aggregate morphologies of Aβ1-42 and Aβ1-42 + QVA1-5 which intensely reinforced the modulatory action of QVA1-5 on the molecular assembly of Aβ1-42. Alamar Blue assay proved QVA1-5 as effective neuroprotectors in SH-SY5Y cell line against Aβ1-42 induced toxicity. Western blot showed increased Aβ1-42 fibrils in SH-SY5Y cells with QVA1-5. In molecular docking, all ligands had identical binding poses in sites 4-6 of Aβ fibril structure (PDB ID: 2M4J), where ligands span across five Aβ monomers that are stacked together and stabilized the fibril formation by hydrophobic interactions with the residues of Aβ monomers. In the molecular dynamic simulations, the lesser RMSD and similar rGyr values for ligands further supported the stability of the ligands inside the binding pocket of 2M4J Aβ fibril. All in all, the present study provides a mechanistic explanation at the atomic level for the impact of QVA1-5 on the Aβ fibril stabilization and shed light for the discovery of drugs that can manipulate the Aβ aggregates formation.