Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India.
School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology, Patiala, Punjab, India.
J Biomol Struct Dyn. 2020 Apr;38(6):1598-1611. doi: 10.1080/07391102.2019.1614093. Epub 2019 May 17.
Alzheimer's disease (AD) is a neurodegenerative disease mainly caused by amyloid-β (Aβ) peptide self-assembly in the brain. During last years, numerous multifunctional small molecules have been designed and synthesized against self-induced Aβ aggregation, metal-induced Aβ 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 Aβ aggregation and BACE1 as well as possessing metal chelating activity and antioxidant property was reported. In the present study, the molecular mechanism of Aβ 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 Aβ monomer by interacting with key central hydrophobic core (CHC) region. BTT significantly enhances helical content from 46% to 57% in Aβ monomer, which, in turn, highlight conservation of non-aggregation prone native structure of Aβ. 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 Aβ participate in binding with BTT. The present study reveals the underlying inhibitory mechanism of BTT against Aβ 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 diseaseAβamyloid-βADTAutoDock 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 area-couplingDec-DETAN1-decanoyl-diethylenetriamineNFTsneurofibrillary tanglesNMRnuclear magnetic resonancePMEparticle mesh ewaldPCprincipal componentPCAprincipal component analysisPDBprotein data bankradius-of-gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationSPCsimple point chargeVMDvisual molecular dynamicsCommunicated by Ramaswamy H. Sarma.
阿尔茨海默病（AD）是一种神经退行性疾病，主要由大脑中的淀粉样β（Aβ）肽自组装引起。在过去的几年中，已经设计和合成了许多多功能小分子，以对抗自诱导的 Aβ聚集、金属诱导的 Aβ聚集、β-分泌酶（BACE1）、乙酰胆碱酯酶（AChE），以及具有金属螯合和抗氧化活性的物质。最近，报道了一种具有多功能活性的双三唑啉三唑（BTT）化合物，可抑制 Aβ聚集和 BACE1，并具有金属螯合和抗氧化性能。在本研究中，使用分子对接和分子动力学（MD）模拟阐明了 BTT 抑制 Aβ聚集的分子机制。MD 分析突出表明，BTT 通过与关键的中央疏水区（CHC）区域相互作用，有效地抑制构象转变并稳定 Aβ单体的天然结构。BTT 使 Aβ单体的螺旋含量从 46%显著增加到 57%，这反过来又突出了 Aβ不易聚集的天然结构的保守性。通过分子力学泊松-玻尔兹曼表面面积（MM-PBSA）方法进行的结合自由能分析突出了 Aβ中残基 Phe4、Leu17、Phe20、Ala21、Ala30、Ile31、Leu34 和 Ile41 与 BTT 结合。本研究揭示了 BTT 抑制 Aβ聚集的潜在抑制机制，并将有助于未来设计更有效的抑制剂。本研究的总体结果将对药物发现科学家阐明阿尔茨海默病 Aβ聚集的分子机制非常有益。缩写词POH2-(1-(3-羟基丙基)-1H-1,2,3-三唑-4-基)苯酚PMorph2-(1-(2-吗啉乙基)-1H-1,2,3-三唑-4-基)苯酚PTMorph2-(1-(2-硫代吗啉乙基)-1H-1,2,3-三唑-4-基)苯酚3D三维AChE乙酰胆碱酯酶AD阿尔茨海默病Aβ淀粉样-βADTAutoDock ToolsATBAutomated Topology BuilderBACE1β-分泌酶BTT双三唑啉三唑CHC中央疏水区HFHartree-FockDSSPDictionary of Secondary Structure of ProteinsFDA食品和药物管理局FEL自由能景观GROMACS GROningen MAchine for Chemical SimulationsLGALamarckian 遗传算法LINCSLINear Constraint SolverMD分子动力学MM-PBSAMolecular Mechanics Poisson-Boltzmann Surface Area-CouplingDec-DETAN1-癸酰基-二乙撑三胺NFTs神经原纤维缠结NMR核磁共振PME粒子网格 ewaldPC主成分分析PCAprincipal 成分分析PDB蛋白质数据银行半径 gyrationRMSD均方根偏差RMSF均方根波动SPC简单点电荷VMD可视化分子动力学由 Ramaswamy H. Sarma 传达。
