No abstract

Amyloid beta (Aβ) peptide aggregation is considered as one of the key hallmarks of Alzheimer’s disease (AD). Moreover, Aβ peptide aggregation increases considerably in the presence of metal ions and triggers the generation of reactive oxygen species (ROS), which ultimately leads to oxidative stress and neuronal damage. Based on the ‘multitarget-directed ligands’ (MTDLs) strategy, we designed, synthesized, and evaluated a novel series of triazole-based compounds for AD treatment via experimental and computational methods. Among the designed MTDLs [4­(a–x)], the triazole derivative 4v exhibited the most potent inhibition of self-induced Aβ42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 μM and also disassembled the preformed Aβ42 aggregates significantly. In addition, compound 4v showed excellent metal chelating ability and maintained copper in the redox-dormant state to prevent the generation of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled the Cu2+-induced Aβ42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v did not show cytotoxicity and was able to inhibit the toxicity induced by Aβ42 aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of 4v with Aβ42 monomer and Aβ42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.

The molecular dynamics simulations results highlighted that the multi-target-directed ligand 6n stabilizes the native α-helix conformation of the Aβ42 monomer and induces a sizable destabilization in the Aβ42 protofibril structure.

Alzheimer’s disease (AD) is a neurological disorder, growing epidemic across worldwide due to no effective medical aid available in the market. AD is known to be directly associated with toxicity...

CuO nanowires exhibited highest catalytic efficiency for the cycloaddition reaction between azide and terminal alkyne, featuring short reaction time, soft reaction conditions and complete regioselectivity.

According to clinical studies, the development of Alzheimer’s disease (AD) is linked to the abnormal aggregation of amyloid-β (Aβ) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils....

Clinical studies have identified that abnormal selfassembly of amyloid-β (Aβ) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer's disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of β-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives 4(a−x), where compound 4v was identified as the most potent inhibitor of Aβ 42 aggregation and disaggregates preformed Aβ 42 fibrils significantly. Moreover, 4v strongly averts the Cu 2+ -induced Aβ 42 aggregation and disaggregates the preformed Cu 2+ -induced Aβ 42 fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aβ 42 aggregation by 4v and disaggregation of preformed Aβ 42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aβ 42 monomer and a pentameric protofibril structure of Aβ 42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aβ 42 monomer and chains D and E of the Aβ 42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aβ 42 monomer into the aggregation-prone β-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson− Boltzmann surface area method revealed an energetically favorable process with ΔG binding = −44.9 ± 3.3 kcal/mol for the Aβ 42 monomer−4v complex. The free energy landscape analysis highlighted that the Aβ 42 monomer−4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ 42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π−π interactions with Phe19 (chain D) of the Aβ 42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aβ 42 protofibril showed the maximum contribution in the binding free energy. The decreased binding affinity and residue−residue contacts between chains D and E of the Aβ 42 protofibril in the presence of 4v indicate destabilization of the Aβ 42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aβ 42 monomer and persuades a destabilization in the protofibril structure of Aβ 42 . The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.

The aberrant deposition of α–Synuclein (α–Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterize the devastating neurodegenerative condition known as Parkinson’s disease (PD). The disruption...