ABSTRACT
Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disease and remains a formidable global health challenge. The current medication for AD gives symptomatic relief and, thus, urges us to look for alternative disease-modifying therapies based on a multitarget directed approach. Looking at the remarkable progress made in peptide drug development in the last decade and the benefits associated with peptides, they offer valuable chemotypes [multitarget directed ligands (MTDLs)] as AD therapeutics. This review recapitulates the current developments made in harnessing peptides as MTDLs in combating AD by targeting multiple key pathways involved in the disease's progression. The peptides hold immense potential and represent a convincing avenue in the pursuit of novel AD therapeutics. While hurdles remain, ongoing research offers hope that peptides may eventually provide a multifaceted approach to combat AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Oxidative Stress , tau Proteins , Animals , Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Cholinesterases/metabolism , Oxidative Stress/drug effects , Peptides/pharmacology , Peptides/therapeutic use , Protein Aggregates/drug effects , Protein Aggregates/physiology , Protein Aggregation, Pathological/drug therapy , Protein Aggregation, Pathological/metabolism , tau Proteins/metabolismABSTRACT
Amyloid-ß (Aß) peptides aggregate spontaneously into various aggregating species comprising oligomers, protofibrils, and mature fibrils in Alzheimer's disease (AD). Disrupting ß-sheet rich neurotoxic smaller soluble Aß42 oligomers formed at early stages is considered a potent strategy to interfere with AD pathology. Previous experiments have demonstrated the inhibition of the early stages of Aß aggregation by baicalein; however, the molecular mechanism behind inhibition remains largely unknown. Thus, in this work, molecular dynamics (MD) simulations have been employed to illuminate the molecular mechanism of baicalein-induced destabilization of preformed Aß42 protofibrils. Baicalein binds to chain A of the Aß42 protofibril through hydrogen bonds, π-π interactions, and hydrophobic contacts with the central hydrophobic core (CHC) residues of the Aß42 protofibril. The binding of baicalein to the CHC region of the Aß42 protofibril resulted in the elongation of the kink angle and disruption of K28-A42 salt bridges, which resulted in the distortion of the protofibril structure. Importantly, the ß-sheet content was notably reduced in Aß42 protofibrils upon incorporation of baicalein with a concomitant increase in the coil content, which is consistent with ThT fluorescence and AFM images depicting disaggregation of pre-existing Aß42 fibrils on the incorporation of baicalein. Remarkably, the interchain binding affinity in Aß42 protofibrils was notably reduced in the presence of baicalein leading to distortion in the overall structure, which agrees with the structural stability analyses and conformational snapshots. This work sheds light on the molecular mechanism of baicalein in disrupting the Aß42 protofibril structure, which will be beneficial to the design of therapeutic candidates against disrupting ß-sheet rich neurotoxic Aß42 oligomers in AD.
Subject(s)
Amyloid beta-Peptides , Flavanones , Molecular Dynamics Simulation , Peptide Fragments , Flavanones/chemistry , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Hydrophobic and Hydrophilic Interactions , Hydrogen Bonding , Humans , Protein Conformation, beta-StrandABSTRACT
The main protease (Mpro) of SARS-CoV-2 is a essential enzyme that facilitates viral transcription and replication. Furthermore, the conservation of Mpro across different variants and its non-overlapping nature with human proteases make it an appealing target for therapeutic interventions against SARS-CoV-2. Multiple inhibitors specifically target Mpro to mitigate the infection caused by SARS-CoV-2. In the current study, successful cloning and expression of SARS-CoV-2 Mpro were achieved using two E. coli hosts, namely BL21-DE3 and BL21-DE3-RIL. By optimizing the conditions for induction, the expression of Mpro in the soluble fraction of E. coli was improved. Subsequently, Mpro was purified using affinity chromatography, yielding significantly higher quantities from the BL21-DE3-RIL strain compared to the BL21-DE3 strain, with the former producing nearly twice as much as the latter. The purified Mpro was further characterized by mass spectrometry, fluorescence spectroscopy and circular dichroism (CD). Through fluorescence quenching studies, it was discovered that both GC376 and chitosan, which are inhibitors of Mpro, induced structural changes in the purified Mpro protein. This indicates that the protein retained its functional activity even after being expressed in a bacterial host. Further, FRET-based assay highlighted that the enzymatic activity of Mpro was significantly reduced in presence of both GC376 and chitosan. Consequently, the utilization of optimal conditions and the BL21-DE3-RIL bacterial host facilitates the cost-effective production of Mpro on a large scale, enabling high yields. This production approach can be applied for the screening of potent therapeutic drugs, making it a valuable resource for drug development endeavors.
Subject(s)
COVID-19 , Chitosan , Humans , SARS-CoV-2/genetics , Escherichia coli , Solubility , Chitosan/metabolism , Endopeptidases/metabolism , Protease Inhibitors/pharmacology , Molecular Docking SimulationABSTRACT
Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with α/ß-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication.
Subject(s)
COVID-19 , Humans , Linagliptin/pharmacology , SARS-CoV-2/metabolism , Sitagliptin Phosphate/pharmacology , Dipeptidyl Peptidase 4/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Protein BindingABSTRACT
Amyloid-ß (Aß) aggregation plays a key role in the pathogenesis of Alzheimer's disease (AD). Along with this, the presence of redox-active metals like Cu2+ further enhances Aß aggregation, oxidative stress, and cellular toxicity. In this study, we have rationally designed, synthesized, and evaluated a series of triazole-peptide conjugates as potential promiscuous ligands capable of targeting different pathological factors of AD. In particular, peptidomimetic DS2 showed the best inhibitory activity against Aß aggregation with an IC50 value of 2.43 ± 0.05 µM. In addition, DS2 disaggregates preformed Aß42 fibrils, chelates metal ions, inhibits metal-mediated Aß aggregation, significantly controls reactive oxygen species production, and reduces oxidative stress. DS2 exhibited very low cytotoxicity and significantly ameliorated the Aß-induced toxicity in differentiated neuroblastoma cells, SH-SY5Y. In addition, alteration in the fibrillary architecture of Aß42 in the absence and presence of DS2 was validated by transmission electron microscopy (TEM) images. To shed light on the inhibitory mechanism of DS2 against Aß aggregation and disassembly of the protofibril structure, molecular dynamics (MD) simulations have been performed. DS2 binds preferentially with the central hydrophobic core (CHC) residues of Aß42 monomer and chains D-E of Aß42 protofibril. The dictionary of secondary structure of proteins analysis indicated a noteworthy increase in the helix content from 38.5 to 61% and, notably, a complete loss of ß-sheet content of Aß42 monomer when DS2 is added to it. DS2 suppressed Aß42 monomer aggregation by preserving helical conformations and was able to reduce the production of aggregation-prone ß-sheet structures, which are consistent with ThT, circular dichroism, and TEM assay that indicate a reduction in the formation of toxic Aß42 aggregated species on the addition of DS2. Moreover, DS2 destabilized the Aß42 protofibril structure by significantly reducing the binding affinity between chains D-E of protofibril, which highlighted the disruption of interchain interactions and subsequent deformation of the protofibril structure. The results of the present study demonstrate that triazole-peptide conjugates may be valuable chemotypes for the development of promising multifunctional AD therapeutic candidates.
Subject(s)
Alzheimer Disease , Neuroblastoma , Humans , Triazoles/pharmacology , Triazoles/chemistry , Amyloid beta-Peptides/metabolism , Alzheimer Disease/metabolism , Molecular Dynamics Simulation , Metals , Peptide Fragments/metabolismABSTRACT
The aberrant deposition of α-synuclein (α-Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterizes the devastating neurodegenerative condition known as Parkinson's disease (PD). The disruption of pre-existing disease-relevant α-Syn fibrils is recognized as a viable therapeutic approach for PD. Ellagic acid (EA), a natural polyphenolic compound, is experimentally proven as a potential candidate that prevents or reverses the α-Syn fibrillization process. However, the detailed inhibitory mechanism of EA against the destabilization of α-Syn fibril remains largely unclear. In this work, the influence of EA on α-Syn fibril and its putative binding mechanism were explored using molecular dynamics (MD) simulations. EA interacted primarily with the non-amyloid-ß component (NAC) of α-Syn fibril, disrupting its ß-sheet content and thereby increasing the coil content. The E46-K80 salt bridge, critical for the stability of Greek-key-like α-Syn fibril, was disrupted in the presence of EA. The binding free energy analysis using the MM-PBSA method demonstrates the favourable binding of EA to α-Syn fibril (ΔGbinding = -34.62 ± 11.33 kcal mol-1). Interestingly, the binding affinity between chains H and J of the α-Syn fibril was significantly reduced on the incorporation of EA, which highlights the disruptive ability of EA towards α-Syn fibril. The MD simulations provide mechanistic insights into the α-Syn fibril disruption by EA, which gives a valuable direction for the development of potential inhibitors of α-Syn fibrillization and its associated cytotoxicity.
Subject(s)
Neurodegenerative Diseases , Parkinson Disease , Humans , alpha-Synuclein/chemistry , Molecular Dynamics Simulation , Ellagic Acid/pharmacologyABSTRACT
According to clinical studies, the development of Alzheimer's disease (AD) is linked to the abnormal aggregation of amyloid-ß (Aß) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils. The most acceptable therapeutic strategy for the treatment of AD is to block the Aß aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH2 (rk10), which acts as a potent inhibitor of Aß aggregation and efficiently disaggregates pre-assembled Aß fibrils. However, the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils remains obscure. To investigate the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils, molecular dynamics (MD) simulations have been performed in the present study. The molecular docking analysis using AutoDock Vina predicted favourable binding of rk10 with the N-terminal and central hydrophobic core (CHC) residues of Aß42 monomer (-5.3 kcal mol-1), and with the residues of chain A of Aß42 protofibril structure (-6.9 kcal mol-1). The MD simulations depicted higher structural stability of Aß42 monomer in the presence of rk10. Notably, rk10 prevented the sampling of ß-sheet rich structures of Aß42 monomer by reducing the side-chain contacts between N-terminal and C-terminal residues of Aß42 monomer. The per-residue binding free energy analysis highlighted the significant contribution of Phe19 and Glu22 of Aß42 monomer in binding with rk10, which corroborate with the 1H NMR (nuclear magnetic resonance) spectra of Aß42 monomer + rk10 complex that depicted a change in the chemical shifts of amide protons of Phe19 and Glu22. Further, rk10 destabilized the Aß42 protofibril structure by lowering the number of interchain hydrogen bonds. The binding free energy analysis predicted lower binding affinity between Aß42 protofibril chains in the presence of rk10 as compared to Aß42 protofibril alone. The insights into the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils will be beneficial for the design and development of potent anti-amyloid inhibitors.
Subject(s)
Alzheimer Disease , Protons , Alzheimer Disease/metabolism , Amides , Amyloid/chemistry , Amyloid beta-Peptides/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Protein Conformation, beta-StrandABSTRACT
Analysis of kinetic and thermodynamic parameters measured for CO-association reaction of Ferrocytochrome c (Ferrocyt c) under variable concentrations of 1-butyl-3-methylimidazolium with varying anion ([Bmim]X) (X = Cl-, I-, Br-, HSO4-) at pH 7 revealed that the low concentration of [Bmim]X (≤0.5 M) constrains the CO-association dynamics of Ferrocyt c and typically follows the order: [Bmim]HSO4 > [Bmim]Cl > [Bmim]Br > [Bmim]I. At relatively higher concentrations (>0.5), the chaotropic action of [Bmim]+ dominates which consequently increases the thermal-fluctuations responsible to denature the protein and thus accelerates the speed of CO-association reaction. Analysis of thermal denaturation curves of Ferrocyt c measured at different concentrations of [Bmim]X revealed that the [Bmim]X decreases the thermodynamic stability of protein and typically follows the order: [Bmim]I > [Bmim]Br > [Bmim]Cl > [Bmim]CH3COO > [Bmim]HSO4, demonstrating that the effect of [Bmim]X on thermodynamic stability of protein is not in accordance to Hofmeister series effect of anions because instead of increasing the kosmotropic anion carrying [Bmim]X ([Bmim]CH3COO and [Bmim]HSO4) also decreases the thermodynamic stability of protein.
Subject(s)
Carbon Monoxide/metabolism , Cytochromes c/metabolism , Imidazoles/metabolism , Ionic Liquids/metabolism , Animals , Cytochromes c/chemistry , Enzyme Stability , Horses , Models, Molecular , ThermodynamicsABSTRACT
Alzheimer's disease (AD), an epidemic growing worldwide due to no effective medical aid available in the market, is a neurological disorder. AD is known to be directly associated with the toxicity of amyloid-ß (Aß) aggregates. In search of potent inhibitors of Aß aggregation, Hamilton and co-workers reported an α-helix mimetic, ADH-31, which acts as a powerful antagonist of Aß42 aggregation. To identify the key interactions between protein-ligand complexes and to gain insights into the inhibitory mechanism of ADH-31 against Aß42 aggregation, molecular dynamics (MD) simulations were performed in the present study. The MD simulations highlighted that ADH-31 showed distinct binding capabilities with residues spanning from the N-terminal to the central hydrophobic core (CHC) region of Aß42 and restricted the conformational transition of the helix-rich structure of Aß42 into another form of secondary structures (coil/turn/ß-sheet). Hydrophobic contacts, hydrogen bonding and π-π interaction contribute to the strong binding between ADH-31 and Aß42 monomer. The Dictionary of Secondary Structure of Proteins (DSSP) analysis highlighted that the probability of helical content increases from 38.5% to 50.2% and the turn content reduces from 14.7% to 6.2% with almost complete loss of the ß-sheet structure (4.5% to 0%) in the Aß42 monomer + ADH-31 complex. The per-residue binding free energy analysis demonstrated that Arg5, Tyr10, His14, Gln15, Lys16, Val18, Phe19 and Lys28 residues of Aß42 are responsible for the favourable binding free energy in Aß42 monomer + ADH-31 complex, which is consistent with the 2D HSQC NMR of the Aß42 monomer that depicted a change in the chemical shift of residues spanning from Glu11 to Phe20 in the presence of ADH-31. The MD simulations highlighted the prevention of sampling of amyloidogenic ß-strand conformations in Aß42 trimer in the presence of ADH-31 as well as the ability of ADH-31 to destabilize Aß42 trimer and protofibril structures. The lower binding affinity between Aß42 trimer chains in the presence of ADH-31 highlights the destabilization of the Aß42 trimer structure. Overall, MD results highlighted that ADH-31 inhibited Aß42 aggregation by constraining Aß peptides into helical conformation and destabilized Aß42 trimer as well as protofibril structures. The present study provides a theoretical insight into the atomic level details of the inhibitory mechanism of ADH-31 against Aß42 aggregation as well as protofibril destabilization and could be implemented in the structure-based drug design of potent therapeutic agents for AD.
Subject(s)
Amyloid beta-Peptides/metabolism , Niacinamide/analogs & derivatives , Niacinamide/metabolism , Peptide Fragments/metabolism , Peptidomimetics/metabolism , Protein Multimerization/drug effects , Amino Acid Sequence , Amyloid beta-Peptides/chemistry , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Protein Binding , Protein Conformation, alpha-Helical/drug effects , ThermodynamicsABSTRACT
Clinical studies have identified that abnormal self-assembly of amyloid-ß (Aß) 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 ß-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 Aß42 aggregation and disaggregates preformed Aß42 fibrils significantly. Moreover, 4v strongly averts the Cu2+-induced Aß42 aggregation and disaggregates the preformed Cu2+-induced Aß42 fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aß42 aggregation by 4v and disaggregation of preformed Aß42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aß42 monomer and a pentameric protofibril structure of Aß42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aß42 monomer and chains D and E of the Aß42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aß42 monomer into the aggregation-prone ß-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 Aß42 monomer-4v complex. The free energy landscape analysis highlighted that the Aß42 monomer-4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aß42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π-π interactions with Phe19 (chain D) of the Aß42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aß42 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 Aß42 protofibril in the presence of 4v indicate destabilization of the Aß42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aß42 monomer and persuades a destabilization in the protofibril structure of Aß42. The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.
ABSTRACT
Amyloid aggregation modulators offer a promising treatment strategy for Alzheimer's disease (AD). We have recently reported a novel di-triazole based compound 6n as a multi-target-directed ligand (MTDL) against AD. 6n effectively inhibits Aß42 aggregation, metal-induced Aß42 aggregation, reactive oxygen species (ROS) generation, and rescues SH-SY5Y cells from Aß42 induced neurotoxicity. However, the underlying inhibitory mechanism remains uncovered. In this regard, molecular dynamics (MD) simulations were performed to understand the effect of 6n on the structure and stability of monomeric Aß42 and a pentameric protofibril structure of Aß42. Compound 6n binds preferably to the central hydrophobic core (CHC) and C-terminal regions of the Aß42 monomer as well as the protofibril structure. The secondary structure analysis suggests that 6n prevents the aggregation of the Aß42 monomer and disaggregates Aß42 protofibrils by sustaining the helical content in the Aß42 monomer and converting the ß-sheet into random coil conformation in the Aß42 protofibril structure. A significant decrease in the average number of hydrogen bonds, binding affinity, and residue-residue contacts between chains D-E of the Aß42 protofibril in the presence of 6n indicates destabilization of the Aß42 protofibril structure. The MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) analysis highlighted favourable binding free energy (ΔGbinding) for the Aß42 monomer-6n and Aß42 protofibril-6n complex. Overall, MD results highlighted that 6n stabilizes the native α-helix conformation of the Aß42 monomer and induces a sizable destabilization in the Aß42 protofibril structure. This work provides theoretical insights into the inhibitory mechanism of 6n against amyloid aggregation and will be beneficial as a molecular guide for structure-based drug design against AD.
Subject(s)
Amyloid beta-Peptides/metabolism , Peptide Fragments/metabolism , Triazoles/chemistry , Amyloid/chemistry , Amyloid/metabolism , Amyloid beta-Peptides/chemistry , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein StabilityABSTRACT
Amyloid beta (Aß) peptide aggregation is considered as one of the key hallmarks of Alzheimer's disease (AD). Moreover, Aß 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 Aß42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 µM and also disassembled the preformed Aß42 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 Aß42 aggregation and disassembled the Cu2+-induced Aß42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v did not show cytotoxicity and was able to inhibit the toxicity induced by Aß42 aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of 4v with Aß42 monomer and Aß42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.
Subject(s)
Amyloid beta-Peptides/metabolism , Chelating Agents/pharmacology , Neuroprotective Agents/pharmacology , Peptide Fragments/metabolism , Protein Multimerization/drug effects , Triazoles/pharmacology , Cell Line, Tumor , Chelating Agents/chemical synthesis , Chelating Agents/metabolism , Copper/chemistry , Drug Design , Humans , Molecular Docking Simulation , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Protein Binding , Reactive Oxygen Species/metabolism , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aß aggregation, metal-induced Aß aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC50â¯=â¯8.065⯱â¯0.129⯵M) against Aß42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50â¯=â¯6.385⯱â¯0.009⯵M). Compound 6n disassembled preformed Aß42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aß42 aggregation and disassembled preformed Cu2+-induced Aß42 aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aß42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aß42 monomer and Aß42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aß42 that play a critical role in Aß42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.