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Small Molecular Inhibitors of Amyloid Β and Α Synuclein Amyloidogenic Aggregation, Toxicity and in Silico Design of Amyloid-Binding Ligands

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Small Molecular Inhibitors of Amyloid Β and Α Synuclein Amyloidogenic Aggregation, Toxicity and in Silico Design of Amyloid-Binding Ligands Small molecular inhibitors of Amyloid β and α Synuclein amyloidogenic aggregation, toxicity and in silico design of amyloid-binding ligands Sukanya Das, M.Sc. Discipline of Pharmacology Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide May 2018 A thesis submitted for the degree of Doctor of Philosophy Table of Contents Abstract .................................................................................................................................. i Declaration........................................................................................................................... iii Acknowledgements ............................................................................................................. iv Statements of Authorship ................................................................................................... vi List of Abbreviations .......................................................................................................... xi Chapter 1 : Introduction ........................................................................................................... 1 1.1 Dementia and neurodegenerative diseases .............................................................. 1 1.1.1 Overview ............................................................................................................. 1 1.1.2 Dementia and Alzheimer’s disease (AD) prevalence ......................................... 2 1.1.3 Prevalence of Parkinson’s disease (PD) ............................................................. 3 1.1.4 Neuropathology of Alzheimer’s disease ............................................................. 4 1.1.5 Neuropathology of Parkinson’s disease .............................................................. 5 1.2 Current treatments for AD and PD ......................................................................... 6 1.3 The amyloidogenic proteins Aβ and αS ................................................................... 7 1.3.1 Amyloidogenesis................................................................................................. 7 1.3.2 The amyloid hypothesis ...................................................................................... 8 1.3.3 Structures of Aβ and αS .................................................................................... 10 1.3.4 Amyloidogenic protein aggregation ................................................................. 12 1.4 Mechanisms of toxicity by Aβ and αS amyloidogenic proteins ......................... 13 1.4.1 Toxicity related to Aβ and αS aggregation ...................................................... 13 1.4.2 Oxidative stress and lipid peroxidation from Aβ and αS aggregation ............. 14 1.4.3 Inflammatory responses associated with Aβ and αS aggregation .................... 14 1.4.4 Other mechanisms of toxicity by Aβ and αS aggregates .................................. 15 1.4.5 Synaptic dysfunction by αS amyloidogenic aggregation .................................. 16 1.5 Different approaches to reduce Aβ and αS accumulation.................................. 18 1.5.1 Reducing Aβ and αS production ....................................................................... 18 1.5.2 Inhibiting Aβ and αS aggregation ..................................................................... 19 1.5.3 Clearance of Aβ and αS aggregates .................................................................. 20 1.6 Natural products as inhibitors of amyloidogenic protein aggregation ............. 20 1.6.1 Advantages of natural products in drug discovery ........................................... 20 1.6.2 Health benefits of natural polyphenols ............................................................. 21 1.6.3 Polyphenols that inhibit amyloidogenic protein aggregation and toxicity ....... 22 1.6.4 Publication 1: Book Chapter ............................................................................. 25 1.6.5 Clinical application of natural products as amyloidogenic protein aggregation inhibitors ............................................................................................................ 29 1.7 Search for new inhibitors of Aβ amyloidogenic aggregation from synthetic origin ....................................................................................................................... 29 1.8 Biochemical and cell-based assays coupled with molecular modelling for identifying new amyloid inhibitors ....................................................................... 30 1.8.1 Monitoring amyloidogenic protein aggregation by Thioflavin T assay ........... 30 1.8.2 Visualisation of amyloidogenic aggregation by Electron Microscopy ............. 31 1.8.3 Probing the structural conversion of αSA53T protein by ion mobility-mass spectrometry ...................................................................................................... 31 1.8.4 Study of neuronal cell viability using the MTT assay for neuroprotection ...... 32 1.8.5 Studying the interaction of molecules with Aβ and αSA53T by molecular docking .............................................................................................................. 33 1.9 Research Aims ........................................................................................................ 34 Chapter 2 : Bioactive polyphenol interactions with β amyloid: a comparison of binding modelling, effects on fibril and aggregates formation and neuroprotective capacity .................................................................................................................. 39 2.1 Publication 2 ........................................................................................................... 41 Chapter 3 : Identification of dibenzyl imidazolidine and triazole acetamide derivatives through virtual screening targeting amyloid beta aggregation and neurotoxicity in PC12 cells .......................................................................................................... 50 3.1 Publication 3 : Appendix A. Supplementary Material ...................................... 53 Chapter 4 : Exploring the structural diversity in inhibitors of α synuclein amyloidogenic folding, aggregation and neurotoxicity ............................................................... 65 4.1 Publication 4 : Appendix A. Supplementary Material ...................................... 67 Chapter 5 : Inhibition of α synuclein and amyloid β aggregation by diverse bioactives reveal a common antiaggregative role of magnolol ........................................... 83 5.1 Introduction ........................................................................................................... 83 5.2 Materials and methods ......................................................................................... 85 5.2.1 Reagents and Chemicals ................................................................................... 85 5.2.2 αSA53T Protein expression and purification .................................................... 86 5.2.3 Thioflavin T kinetic assay of αSA53T and Aβ1-42 fibrillisation ....................... 86 5.2.4 Transmission Electron Microscopy of Aβ fibrils and aggregates ..................... 87 5.2.5 Computational modelling of bioactive optimized conformation binding to Aβ1-42 and αSA53T ........................................................................................... 88 5.2.6 Statistical Analysis ............................................................................................ 89 5.3 Results .................................................................................................................... 89 5.3.1 Effects of bioactives on αSA53T and Aβ1-42 fibrillisation ................................ 89 5.3.2 Transmission Electron Microscopy of αSA53T and Aβ1-42 fibrils and aggregates ........................................................................................................ 92 5.3.3 Molecular modelling of bioactive interactions with αSA53T and Aβ17-42........ 94 5.4 Discussion............................................................................................................... 97 5.5 Conclusion ........................................................................................................... 101 Chapter 6 : Molecular docking guided design of novel amyloid binding ligands using natural polyphenols and a synthetic heterocyclic ring system as templates ...................... 102 6.1 Introduction and background ............................................................................ 102 6.1.1 Ligand-based drug design ............................................................................... 102 6.1.2 Application of pharmacophore-based drug design for Aβ .............................. 103 6.1.3 Virtual screening ............................................................................................. 104 6.1.4 A combined approach: pharmacophore-based drug design with virtual screening ........................................................................................................ 105 6.1.5 The neolignan biphenyl as template for anti-Aβ ligand design ...................... 106 6.2 Methodology ........................................................................................................ 108 6.2.1 Design strategy for honokiol-derivatives using molecular docking ............... 108 6.2.2 Computational methods .................................................................................
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