Inhibition of Alzheimer’s amyloid-β₄₂ peptide aggregation by a bi-functional bis-tryptoline triazole: key insights from molecular dynamics simulations

Alzheimer’s disease (AD) is a neurodegenerative disease mainly caused by amyloid-β42 (Aβ42) peptide self-assembly in the brain. During last years, numerous multifunctional small molecules have been designed and synthesized against self-induced Aβ42 aggregation, metal-induced Aβ42 aggregation, β-secretase (BACE1), acetylcholinesterase (AChE) as well as possessing metal chelating and antioxidant activities. Recently, a bi-functional bis-tryptoline triazole (BTT) compound displaying multifunctional activity against Aβ42 aggregation and BACE1 as well as possessing metal chelating activity and antioxidant property was reported. In the present study, the molecular mechanism of Aβ42 aggregation inhibition by BTT was elucidated using molecular docking and molecular dynamics (MD) simulations. MD analysis highlighted that BTT effectively inhibits conformational transition and stabilize the native structure of Aβ42 monomer by interacting with key central hydrophobic core (CHC) region. BTT significantly enhances helical content from 46% to 57% in Aβ42 monomer, which, in turn, highlight conservation of non-aggregation prone native structure of Aβ42. The binding free energy analysis by molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) method highlighted that Phe4, Leu17, Phe20, Ala21, Ala30, Ile31, Leu34, and Ile41 residues of Aβ42 participate in binding with BTT. The present study reveals the underlying inhibitory mechanism of BTT against Aβ42 aggregation and will aid in the future design of more potent inhibitors. The overall findings from the present study will be highly beneficial for the drug discovery scientists in the elucidation of the molecular mechanism of Alzheimer’s Aβ aggregation. AbbreviationsPOH2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenolPMorph2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenolPTMorph2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol3Dthree dimensionalAChEAcetylcholinesteraseADAlzheimer’s diseaseAβ42amyloid-β42ADTAutoDock ToolsATBAutomated Topology BuilderBACE1β–secretaseBTTbis-tryptoline triazoleCHCcentral hydrophobic coreHFHartree–FockDSSPdictionary of secondary structure of proteinsFDAFood and Drug AdministrationFELfree energy landscapeGROMACSGROningen MAchine for Chemical SimulationsLGALamarckian Genetic AlgorithmLINCSLINear Constraint SolverMDmolecular dynamicsMM–PBSAmolecular mechanics Poisson–Boltzmann surface area3JNH-HαJ-couplingDec–DETAN1–decanoyl-diethylenetriamineNFTsneurofibrillary tanglesNMRnuclear magnetic resonancePMEparticle mesh ewaldPCprincipal componentPCAprincipal component analysisPDBprotein data bankRgradius–of–gyrationRMSDroot-mean-square deviationRMSFroot–mean–square fluctuationSPCsimple point chargeVMDvisual molecular dynamics 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol three dimensional Acetylcholinesterase Alzheimer’s disease amyloid-β42 AutoDock Tools Automated Topology Builder β–secretase bis-tryptoline triazole central hydrophobic core Hartree–Fock dictionary of secondary structure of proteins Food and Drug Administration free energy landscape GROningen MAchine for Chemical Simulations Lamarckian Genetic Algorithm LINear Constraint Solver molecular dynamics molecular mechanics Poisson–Boltzmann surface area J-coupling N1–decanoyl-diethylenetriamine neurofibrillary tangles nuclear magnetic resonance particle mesh ewald principal component principal component analysis protein data bank radius–of–gyration root-mean-square deviation root–mean–square fluctuation simple point charge visual molecular dynamics Communicated by Ramaswamy H. Sarma The molecular mechanism of inhibition of Aβ42 self-assembly by a bi-functional bis-tryptoline triazole (BTT) compound has been investigated using molecular dynamics (MD) simulations. MD simulations reveal that reduced Aβ42 aggregation in presence of BTT is linked to a significant increase in the overall helix content from 46% to 57%, which, in turn, highlight conservation of non-aggregation prone native structure of Aβ42.