| Titre : | Enzyme-substrate interactions study using molecular modeling methods: The case of neurodegenerative diseases -Alzheimer’s disease. |
| Auteurs : | Rania Kherachi, Auteur ; Ismail Daoud, Directeur de thèse ; Nadjib Melkemi, Directeur de thèse |
| Type de document : | Thése doctorat |
| Editeur : | Biskra [Algérie] : Faculté des Sciences Exactes et des Sciences de la Nature et de la Vie, Université Mohamed Khider, 2025 |
| Format : | 1VOL.(125p) / ill.couv.ill.en coul / 30cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Mots-clés: | Alzheimer's disease, AChE, Spiroox-indolepyrrolidine derivatives,Docking/dynamique moléculaire, Bioisosteric, ADME-T |
| Résumé : |
This dissertation reports the findings of a research project focused on enhancing our
comprehension of inhibitors for Alzheimer's disease. Acetylcholinesterase is a prominent Alzheimer's therapeutic target. Some novel spiroox- indolepyrrolidine derivatives have been produced and demonstrated to be antibacterial and acetylcholinesterase inhibitors. This study compares 35 compounds in this series as acetylcholinesterase inhibitors, to clinical trials using molecular docking/dynamics simulations, MEP analysis, bioisosteric replacement, and ADME-T prediction. Molecular docking studies elucidate the interaction between spirooxindolepyrrolidine derivatives and the AChE receptor, demonstrating that compounds L27 and L28 display significant binding affinity, with energy scores of -5.858 and -5.961 kcal/mol, respectively. The results were corroborated by the negligible conformational alterations noted during molecular dynamics simulations of the AChE-L27 and AChE-L28 complexes, as opposed to those observed with tacrine and Donepezil. Furthermore, a bioisosteric substitution approach resulted in the creation of two novel analogs for each compound, which exhibited low energy scores and a considerable number of hydrogen bonds. The predictions regarding ADME-Tox and the physicochemical characteristics of L27 and L28 indicate their promise as drug candidates, particularly in terms of favorable oral bioavailability. Generally speaking, the integration of MEP analysis with molecular docking, dynamics studies and ADME-Tox predictions substantiates the identification of compounds as inhibitors. In summary, the in silico analysis suggests that L27, L28, and their analogs could function as potent inhibitors for Alzheimer's disease. |
| Sommaire : |
List of works ......................................................................................................................... i List of main abbreviations .................................................................................................. iii List of Figures .......................................................................................................................v List of Tables ..................................................................................................................... vii GENERAL INTRODUCTION ............................................................................................1 References .............................................................................................................................4 CHAPTER I: THE METHODS OF MODELLING PROTEIN-LIGAND INTERACTIONS 1. An overview of computer-aided drug design (CADD) .................................................6 2. Virtual screening in silico ..............................................................................................7 3. The CADD classification scheme ..................................................................................8 3.1. Ligand-Based Drug Design (LBDD) ......................................................................8 3.1.1. Quantitative structure-activity relationships (QSAR) .....................................9 3.1.2. Conceptual Density Functional Theory (DFT) ............................................... 10 3.1.3. Drug Design Development Steps ..................................................................... 11 3.1.4. The Procedure of Drug Discovery .................................................................. 12 3.1.5. Computer Simulation for Drug Design .......................................................... 13 3.1.6. Molecular Modelling and Energy Minimization ............................................ 13 3.2. Structure-based drug Discovery (SBDD) ............................................................ 14 3.2.1. Molecular Docking .......................................................................................... 14 3.2.1.1. Searching Algorithm .............................................................................. 16 3.2.1.2. Scoring Functions (SFs) ......................................................................... 17 3.2.1.3. Types of molecular docking ................................................................... 20 3.2.1.4. Steps involved in Molecular Docking .................................................... 21 3.2.1.4.1. Ligand preparation .............................................................................. 21 3.2.1.4.2. Protein Preparation ............................................................................. 22 3.2.1.4.3. Binding Site Detection ......................................................................... 22 3.2.1.4.4. Docking Validation .............................................................................. 22 3.2.2. Molecular Dynamics Simulation (MD) ........................................................... 23 4. Quantitative Molecular Electrostatic Potential Analysis ........................................... 24 5. ADMET Prediction ..................................................................................................... 24 5.1. Drug-likeness and rule-of-five .............................................................................. 28 References ........................................................................................................................... 29 OVERVIEW OF ALZHEIMER’S DISEASE AND ITS TARGETS PART 01:ALZHEIMER’S DISEASE ................................................................................ 38 1. INTRODUCTION ....................................................................................................... 38 2.1. Historical background .......................................................................................... 38 2.2. Epidemiology ........................................................................................................ 39 3. Neuropathological aspects of Alzheimer’s disease ..................................................... 40 3.1. Pathophysiology .................................................................................................... 40 3.1.1. Neurological changes ....................................................................................... 42 3.1.2. Amyloid Plaques and Neurofibrillary Tangles ............................................... 42 3.1.3. Neuroinflammation and Oxidative Stress ...................................................... 43 3.1.4. Neurotransmitter Alterations ......................................................................... 43 3.2. Symptoms ............................................................................................................. 44 3.2.1. Early symptoms ............................................................................................... 44 3.2.2. Progression to Advanced Symptoms .............................................................. 45 3.2.3. Mild Cognitive Impairment (MCI) ................................................................. 46 3.2.4. Moderate and Severe Alzheimer..................................................................... 46 3.3. Etiology and Risk Factors .................................................................................... 46 3.3.1. Genetic predispositions (APOE-e4 and rare mutations)................................ 46 3.3.2. Age-Related Risks ........................................................................................... 47 3.3.3. Lifestyle Factors .............................................................................................. 47 3.3.4. Medical Comorbidities .................................................................................... 48 3.3.5. Environmental and Toxic Exposures ............................................................. 48 3.4. Therapeutic interventions .................................................................................... 48 PART 02: THERAPEUTIC TARGETS ............................................................................ 49 1. Treatment and Management....................................................................................... 49 1.2. Pharmacological Treatments ............................................................................... 50 1.2.1. Acetylcholinesterase ........................................................................................ 50 1.2.1.1. Neurotransmission ................................................................................. 50 1.2.1.2. Involvement of ACHE in Alzheimer’s Disease ...................................... 51 1.2.1.2.1. ACHE Inhibitors ................................................................................. 51 1.2.2. Butylcholinesterase.......................................................................................... 52 1.2.2.1. Involvement of BuCHE in Alzheimer’s Disease .................................... 53 1.2.2.1.1. BuCHE Inhibitors................................................................................ 53 1.2.3. NMDA Receptor Antagonists ......................................................................... 54 1.2.4. Emerging Therapies ........................................................................................ 55 1.3. Obstacles in the Advancement of Novel Inhibitors Alzheimer's. ....................56 References ........................................................................................................................... 58 CHAPTER III: Investigation of spirooxindole-pyrrolidine derivatives as acetylcholinesterase inhibitors using molecular docking/dynamics simulations, bioisosteric replacement, MEP, and ADME/Tox properties 1. Introduction ................................................................................................................. 64 1.1. Materials and Methods......................................................................................... 65 2.1. Target and Compounds Preparations ................................................................. 66 2.1.1. Target Preparation .......................................................................................... 66 2.1.2. Compounds Preparation ................................................................................. 66 2.2. Computational Methods ....................................................................................... 68 2.2.1. Molecular Docking Protocol and Validation .................................................. 68 2.2.2. Molecular Dynamics (MD) Simulation .......................................................... 69 2.2.3. Molecular Electrostatic Potential (MEP) Surface Analysis and Bioisosteric Replacement ................................................................................................................ 69 2.2.4. ADME-T Prediction and Chemical Properties .............................................. 70 3. Results and Discussion ................................................................................................ 70 3.1. Molecular Docking Analysis ................................................................................ 70 3.2. Molecular Dynamics Simulation .......................................................................... 73 3.2.1. Thermodynamic Properties ............................................................................ 73 3.3. Molecular Electrostatic Potential Map Analysis ................................................. 78 3.4. Bioisosteric Analogues .......................................................................................... 80 3.5. Evaluation of the ADME-T Properties and Drug-Likeness ................................ 81 3.5.1. Drug-likeness Evaluation ................................................................................ 81 3.5.2. ADME Properties ........................................................................................... 82 3.6. Comparative Study ............................................................................................... 84 References ........................................................................................................................... 87 GENERAL CONCLUSION ............................................................................................... 96 Appendix A ......................................................................................................................... 98 Appendix B ....................................................................................................................... 105 |
| Type de document : | Thése doctorat |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/128 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
