Insights into the Benzodihydrofuran Derivative-Induced Conformational and Structural Changes in the Alzheimer’s Disease-Associated Amyloid-β Peptide

Abstract

The progression of Alzheimer’s disease (AD) is linked to the misfolding and aggregation of amyloid−β (Aβ) monomers into neurotoxic soluble oligomers, protofibrils, and ultimately mature fibrils. The most effective therapeutic approach for treating AD is to inhibit Aβ42 aggregation. Metal complexes and small molecules have been identified as promising inhibitors to combat self–aggregation of Aβ42 monomer. A binuclear metal complex PtRu–1([Ru(bpy)2(dpp)PtCl2]Cl2), containing PtII and RuII metal centers, has been previously reported to inhibit the Aβ42 aggregation in early stages. Thioflavin–T (ThT) assay revealed that incubation of Aβ42 with equimolar or 2−fold molar excess of PtRu–1 led to a 90% decrease in ThT fluorescence, highlighting inhibitory potential against Aβ42 aggregation. Despite comprehensive experimental investigations, the molecular interactions and binding mechanism underlying the inhibitory capacity of Pt−Ru1 on Aβ42 aggregation remain unidentified. Thus, an attempt was made to examine the molecular mechanism by which Pt−Ru1 inhibits the aggregation of Aβ42 monomer. The molecular docking results depict favourable binding (–6.45 kcal/mol) of Pt−Ru1 to Aβ42 monomer influenced by hydrogen bonds, hydrophobic contacts, and π−π stacking interactions. Sánchez et al. synthesized 15 chalcone derivatives using Claisen–Schmidt condensation by utilizing a natural benzodihydrofuran compound, i.e., fomannoxine. Fluorine substitution was found to significantly enhance cytoprotective activity and reduce the aggregation rate of Aβ, making them promising therapeutic candidates. ThT fluorescence analysis reveals that co-incubation of chalcone−3c with Aβ led to a reduction in fluorescence intensity. Notably, chalcone−3c enhanced cell viability by 50%, thereby reducing cytotoxicity and showing no cytotoxic effect at different concentrations. Thus, molecular docking as well as molecular dynamics (MD) simulations were employed to examine the inhibitory mechanism of chalcone3c against self–aggregation of Aβ42 monomer. The molecular docking results indicated a favorable interaction of chalcone−3c with the Aβ42 monomer, exhibiting a binding energy of −6.7 kcal/mol. The RMSD and RMSF evaluations exhibited a decrease in conformational variations in the Aβ42 monomer following the inclusion of chalcone−3c. An increase in helix content was detected in the Aβ42 monomer, rising from 20.2 ± 1.6 % to 33.8 ± 1.5 %, indicating a reduction in the aggregation tendency of the Aβ42 monomer in the presence of chalcone−3c. Additionally, the intramolecular hydrogen bonds rise from 21.37 ± 0.96 to 22.19 ± 1.05 with the addition of chalcone−3c, supporting the enhancement of the helical conformation of Aβ42 monomer. Contact map analysis revealed reduced aggregation tendency of Aβ42 monomer on the incorporation of chalcone−3c due to reduction in residue interaction in the central hydrophobic core (CHC) and C−terminal region. PCA, FEL, and conformational clustering studies highlight higher conformational homogeneity in Aβ42 monomer in the presence of chalcone−3c, which indicates lower fibrillation propensity in Aβ42 monomer. The illumination of the molecular interactions between Aβ42 monomer and chalcone−3c provides critical insights for the strategic development of more effective aggregation inhibitors as prospective therapeutic candidates against Aβ aggregation in AD.