| Titre : | Contribution à la modélisation des biomolécules et leurs interactions : Cas des inhibiteurs de la monoamine oxydase B dans la maladie de Parkinson |
| Auteurs : | Sana Afroukh, Auteur ; Rania Kherachi, Auteur ; Ismail Daoud , Directeur de thèse |
| Type de document : | Monographie imprimée |
| Editeur : | Biskra [Algérie] : Faculté des Sciences Exactes et des Sciences de la Nature et de la Vie, Université Mohamed Khider, 2020 |
| Format : | 1 vol. (101 p.) / couv. ill. en coul. / 30 cm |
| Langues: | Anglais |
| Mots-clés: | Parkinson's disease,Molecular Docking,Molecular Dynamic,ADME,Interaction. |
| Résumé : |
Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease. Several studies have been conducted to discover new and effective drugs for this rapidly spreading disease, knowing that, to this day, no medicine has been discovered to treat this disease, but there have been attempts to reduce its severity. In order to study the inhibition of enzymes involved in this disease and to identify novel inhibitors, our work focused to use molecular modeling methods based on molecular docking and molecular dynamics using MOE software, as well as by an estimation of the ADME properties. Our discussion is based on two parameters: energy score and distances of interactions between active site residues of MAO B and a series of 4-(benzyloxy) phenyl and biphenyl-4-yl derivatives. After the simulations and according to the comparison between the results of the two previous methods, the compounds L30 and L38 selected to be the best inhibitors of MAO-B and more, both compounds respect the Lipinski, Veber, and Egan rules, they are able to cross the BBB, and they may behave the potential to be used in the development of novel pharmacological agents for the treatment of patients with PD. |
| Sommaire : |
Table list List of Figures List of main abbreviation General introduction 1 References 4 CHAPTER I: MOLECULAR MODELING 1. Introduction 5 2. Molecular Modeling Method 5 2.1.Quantum Methods (QM) 5 2.1.1. ab initio Methods (Hartree-Fock, Roothaan) 6 2.1.2. Density Functional Theory 7 2.2.Semi Empirical methods 8 2.3.Non Quantum Methods 9 2.3.1. Molecular Mechanics 9 a. Term of the force field 10 b. Term of linked atoms 12 c. Interaction energy between unbound atoms 14 d. Different force fields in molecular mechanics 16 e. Minimization of steric energy 17 2.3.2. Molecular Dynamics 18 a. Molecular Dynamics calculation 18 b. Applications of Dynamic molecular 19 2.3.3. Molecular Docking 19 a. Different types of Interactions 20 b. General protocol of docking 21 c. Molecular docking programs 22 3. ADME 23 a. Pharmacokinetics 24 b. Absorption, Distribution, Metabolism, Elimination (ADME) 24 ✓ Absorption 24 ✓ Distribution 25 ✓ Metabolism 25 ✓ Elimination 26 References 27 CHAPTER II : Proteins, Enzymes and Amino acids PART (A) Proteins, enzymes and amino acids 1. Introduction 34 2. The proteins 34 2.1. Definition of proteins 35 2.2. The peptide bond 36 2.3.Protein structure 37 a. Primary structure 38 b. Secondary structure 38 c. Tertiary structure 40 d. Quaternary structure 41 2.4.Protein functions 42 3. The enzymes 43 3.1.Classification of enzymes 44 3.2.Nomenclature 44 3.3.Notions of specificity 45 3.4.The Active Site 46 3.5.Cofactors 46 3.6.Enzyme-Substrate Complex (E-S) 47 3.7.Enzymatic Inhibition 48 3.8.Different kinetic types of enzyme inhibitors 48 3.8.1. Reversible inhibitors 49 a. Competitive inhibition 49 b. Incompetitive (or anti-competitive) inhibition 49 c. Non-competitive or mixed inhibition 50 3.8.2. Irreversible inhibitors 51 4. Amino acids 52 4.1.Classification 52 a. Non-polar amino acids 53 b. Polar, uncharged amino acids 53 PART (B) Parkinson’s disease 5. Parkinson’s disease 54 5.1.History of Parkinson's disease 54 5.2.Causes of Parkinson’s disease 54 a. Environmental factors 54 b. Genetic factors 55 5.3.Pathophysiology of the disease 55 a. Premature selective loss of dopamine neurons 56 b. The accumulation of Lewy bodies, composed of α-synuclein 57 5.4.Monoamine oxidase 58 a. Isoforms 58 b. MAO-A 58 c. MAO-B 59 5.5.Symptoms of Parkinson’s disease 60 a. The motor symptoms 60 b. The non-motor symptoms 62 5.6.Treatment of Parkinson’s disease 62 a. Levodopa (L-dopa) 62 b. Dopaminergic agonists 63 c. Enzyme inhibitor 63 d. Surgery 64 References 66 CHAPTERIII : RESULT AND DISCUSSION 1. Introduction 72 2. Materials and methods 74 2.1.Target and Compounds preparations 74 2.1.1. Target Preparation 74 2.1.2. Compounds preparation 75 3. Computational approach 79 3.1.Molecular Docking Protocol 79 3.1.1. Default parameters and steps of Molecular Docking 79 3.2.Molecular Dynamics (MD) Simulation 80 3.3.ADME predictions 80 4. Results and Discussion 80 4.1.Docking and Pose Analysis 80 4.1.1. Active site residues identifications of target 80 4.1.2. Interactions of compounds with MAO-B target and calculation of binding free energy 81 4.2.Analysis on molecular dynamic simulations 87 4.2.1. Stabilities and flexibilities of the four simulation systems 87 4.3.In silico evaluation of the ADME properties and drug-likeness 93 References 95 General conclusion 101 Annex |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| MCH/423 | Mémoire master | bibliothèque sciences exactes | Consultable |
