| Titre : | Contribution à la découverte de médicaments par une étude computationnelle de plusieurs séries de molécules hétérocycliques |
| Auteurs : | Mebarka Ouassaf, Auteur ; Salah Belaidi, 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, 2019 |
| Format : | 1 vol. (119 p.) / 30 cm |
| Langues: | Français |
| Langues originales: | Français |
| Mots-clés: | 1,2,3-triazole,aromatase inhibitory,density functional theory,QSAR,MLR,ADMET,docking molecular |
| Résumé : |
Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work a fundamental and original research was made on the molecule of triazole heterocyclic, whose the aim is to predict the reactivity and biological activity studied of the compound. It is based on different computational and approaches used in computer aided -drug-design. (SPR, QSAR, molecular docking, ADMET). A study of structure – property relationships (SPR) for 1,2,3 triazole derivatives has been carried. A linear quantitative structure activity relationship model is obtained using Multiple Linear Regression (MLR) analysis as applied to a series of triazole derivatives with inhibitory activity of the aromatase. The accuracy of the proposed MLR model is illustrated using the following evaluation techniques: cross validation, and external test. Docking process, the interaction and binding of ligands – protein were done and visualized using software Molegro Virtual Docking. Molinspiration and ADMETSAR web servers used to calculate ADMET and physicochemical properties of the target compounds respectively. The results are reported and discussed in the present investigation. A close agreement with experimental results was found which improves the affinity of the present work. |
| Sommaire : |
ACKNOWLEDGMENTS TABLE OF CONTENTS LIST OF FIGURES LIST OF TABLES LIST OF ABBREVIATIONS GENERAL INTRODUCTION ........................................................................................................... 1 REFERENCES..................................................................................................................... CHAPETR I: THE TRIAZOLE AND THE AROMATASE INHIBITION FOR BREAST CANCER TREATMENT 1. INTRODUCTION .......................................................................................................................... 5 2. THE TRIAZOLE ............................................................................................................................ 6 2.1 Triazole ring ........................................................................................................................ 6 2.2 Synthetic strategies ............................................................................................................. 7 2.3 Biologically Active Derivatives .......................................................................................... 9 2.4. Other Applications ........................................................................................................... 10 3. AROMATASE INHIBITION FOR BREAST CANCER TREATMENT .................................... 11 3.1 What Is Breast Cancer? .................................................................................................. 11 3.2 Breast cancer molecular subtypes .................................................................................. 12 3.2.1 Hormone Receptor-Positive Breast Cancer .................................................... 12 3.2.2 HER2-Positive Breast Cancer ........................................................................ 13 3.2.1 Triple-Negative Breast Cancer ....................................................................... 13 3.3 Treatment options ........................................................................................................... 14 3.3.1 Hormone therapy for breast cancer ................................................................ 14 3.3.2 Drugs That Block Estrogen ............................................................................ 15 3.3.3 Drugs That Lower Estrogen Levels ................................................................ 15 3.4 What is an aromatase inhibitor and how does it work? .................................................. 16 3.5 The overall structure of aromatase ................................................................................. 16 3.6 Types of aromatase inhibitors ........................................................................................ 18 3.7 Mechanisms of action ..................................................................................................... 20 4. REFERENCES ................................................................................................................... 21 CHAPTER II: COMPUTATIONAL APPROACHES FOR DRUG DESIGN AND DISCOVERY 1. INTRODUCTION ........................................................................................................................ 28 2. COMPUTER-AIDED DRUG DESIGN BASIC PRINCIPLES ................................................... 28 2.1. Quantum Mechanics and Molecular Mechanics .............................................................. 28 2.2. Force Fields...................................................................................................................... 29 2.3. Molecular dynamics ......................................................................................................... 30 2.3.1. Energy-Minimizing Procedures ...................................................................... 30 2.3.2. Steepest Descent Method ................................................................................. 31 2.3.3. Conjugate Gradient Method ............................................................................. 31 3. DRUG-LIKE PROPERTIES ........................................................................................................ 32 4. RULES FOR DRUG DISCOVERY ............................................................................................. 33 4.1 Lipinski Rules (Oral drug properties) .............................................................................. 33 4.2 Veber Rules....................................................................................................................... 34 5. STRATEGIES OF IN SILICO DESIGN ...................................................................................... 34 5.1 Ligand-Based Drug Design .............................................................................................. 34 5.1.1 Quantitative structure-activity relationship ....................................................... 34 5.1.2 The data to model. ............................................................................................. 35 5.1.3 Molecular Descriptors ....................................................................................... 35 5.1.4 Statistical methods used in QSAR analysis ...................................................... 36 5.1.5 Validation of the QSAR model ......................................................................... 37 5.1.6 Evaluation of the model .................................................................................... 40 5.2 Structure-Based Drug Design Strategies SBDD .................................................................... 40 5.2.1 Definition Molecular docking ................................................................................. 41 5.2.2 Different Types Of Interactions ............................................................................... 41 5.2.3 Types of docking ........................................................................................................ 42 5.2.4 Mechanics of docking ............................................................................................... 42 5.2.5 Major steps involved in mechanics of molecular docking ................................ 43 6. REFERENCES ............................................................................................................... 45 CHAPETR III: DRUG LIKENESS SCORING AND STRUCTURE ACTIVITY/PROPERTY RELATIONSHIPS 1. INTRODUCTION ........................................................................................................................ 49 2. MATERIAL AND METHODS .................................................................................................... 50 3. RESULTS AND DISCUSSION ................................................................................................... 50 3.1 Geometric and electronic structure of 1 h-1,2,3-triazole .................................................. 50 3.2 Geometric and electronic structure of 2 h-1,2,3-triazole .................................................. 52 3.3 Molecular electrostatic potential ....................................................................................... 55 3.4 Substitution effect on 2h-1,2,3-triazole structure ............................................................. 56 3.5 Structure activity/property relationships of aromatase inhibitory activity of substituted 1,2,3-triazole ............................................ 63 3.6 Drug-likeness properties of 1,2,3-triazole derivatives ...................................................... 68 4. CONCLUSION ......................................................................................................................... 71 5. REFERENCES ............................................................................................................................. 72 CHAPETR IV: QSAR MODEL FOR PREDICTING THE AROMATASE INHIBITION ACTIVITY OF 1.2.3 TRIAZOLE DERIVATIVES 1 INTRODUCTION ......................................................................................................................... 77 2 MATERIALS AND METHODS ................................................................................................... 78 2.1 Data set ........................................................................................................................... 78 2.2 Descriptors generation .................................................................................................... 80 2.3 Regression analysis ........................................................................................................ 83 2.4 Validation of the qsar model .......................................................................................... 83 3 RESULTS AND DISCUSSION .................................................................................................... 83 4 CONCLUSION .............................................................................................................................. 90 5 REFERENCES ............................................................................................................................... 91 |
| Type de document : | Thése doctorat |
| En ligne : | http://thesis.univ-biskra.dz/id/eprint/4489 |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/68 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
