| Titre : | Computer-aided design of a few series of heterocyclic molecules for therapeutic purposes |
| Auteurs : | Sihem Aggoun, Auteur ; Salah Belaidi, Directeur de thèse ; Lazhar BOUCHLALEG, 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.(103p) / 30cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Mots-clés: | 1,4-dihydropyridine, Calcium Channel Blockers, QSAR, DFT, ANN, MLR. |
| Résumé : |
Artificial neural networks (ANNs) are useful for predicting biological activities from large datasets of molecules. Unlike traditional statistical methods such as regression analysis, ANNs allow the study of complex and nonlinear relationships such as QSAR studies. Here, we use artificial neural network and multiple linear regression (MLR) methods to generate QSAR models for Calcium Channel Blockers activity of a series of 1,4-dihydropyridine derivatives molecules. The molecular descriptors were calculated by using Density Functional Theory (DFT) method at the B3LYP/6-31G+ (d, p) level. The statistical analyses indicate that the predicted values are in good agreement with the experimental results for both the training and test sets using either MLR or ANN. In addition, we used molecular docking to determine the binding energies, and ligand-protein interactions between these compounds and their biological target. |
| Sommaire : |
ACKNOWLEDGMEN CONTENTS LIST OF FIGURES LIST OF TABLES LIST OF ABBREVIATIONS GENERAL INTRODUCTION ......................................................................................... 10 REFERENCES ................................................................................................................. 13 CHAPTER I : DIHYDROPYRIDINES (DHPS) AND THEIR USE IN THE HYPERTENSIVE TREATMENT I.1. INTRODUCTION ...................................................................................................... 16 I.2- DIHYDROPYRIDINE DERIVATIVES ..................................................................... 17 I.2.1. Classification ............................................................................................. 17 I.2.1.1. Compounds with predominant vascular effects ....................................... 17 I.2.1.2. Compounds with vascular and cardiac effects ....................................... 17 I.2.1.3. Calcium Channel Blocker (CCB) .......................................................... 18 I.2.1.3. a . Pharmacological Characteristics ...................................................... 19 I.2.1.3. b . Therapeutic Uses ..............................................................................20 I. 3. HYPERTENSION .....................................................................................................20 I. 3.1. High blood pressure (hypertension) ...........................................................21 I. 3.2. Symptoms of high blood pressure ............................................................. 22 I. 3.3. Causes of arterial hypertension .................................................................22 I. 3. 4. Complications of high blood pressure ...................................................... 23 I. 3. 5. Medical treatment .................................................................................. 23 I. 4. CONCLUSION .......................................................................................................... 26 REFERENCES ............................................................................................. 27 CHAPTER II: DEVELOPMENT , VALIDATION AND APPLICATION OF QSAR/QSPR METHODS .1. INTRODUCTION ...................................................................................................... 30 II.2. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS / PROPERTY QSAR/QSPR .............................................................................................................................. 30 II.2.1. Definition ......................................................................................................... 30 II.2.2. Principle........................................................................................................... 30 II.2.3. Global strategy ............................................................................................... 31 II.3. OECD principles of validity of QSAR/QSPR models ........................................... 32 II.4. Molecular descriptors ........................................................................................... 33 II. 4.1. Introduction...................................................................................................... 33 II.4. 2. Types of descriptors ......................................................................................... 33 II.4.2.1. 1-D descriptors ............................................................................................... 34 II.4.2.2. 2-D descriptors ............................................................................................... 35 II.4.2.3. 3-D descriptors ............................................................................................... 34 II.4.2.3.1 Geometric descriptors ................................................................................... 34 II.4.2.3.2. Physico-chemical descriptors ...................................................................... 36 II.4.2.3.3. Quantum/electronic descriptors................................................................... 37 II.4.2.3.4. Thermodynamic descriptors ........................................................................ 38 II.4.2.4. 4-D descriptors .............................................................................................. 38 II.5. STATISTICAL METHODS................................................................................ 39 II.5.1. Definition.............................................................................................................. 39 II.5.2. Application areas ............................................................................................ 39 II.5.3. Statistical methods ...........................................................................................39 II.5.3.1. Descriptive statistics ..................................................................................... 39 II.5.3.2. Decision-making or predictive statistics ......................................................... 40 II.5.3.2.1. Multiple Linear Regressio (MLR) ...............................................................40 II.5.3.2.2. Multiple nonlinear regression (MNLR) ...................................................... 40 II. 5.3.2.3. The partial least squares regression PLS………………………………………40 II.5.3.2.4. Artificial Neural Networks (ANN)……………………………………………...41 II. 6. VALIDATION METHODS………………………………………………………….45 II. 6. 1. Model Coefficients and Standard Statistical Tests ................................................46 II. 6. 1.1. Correlation Coefficient r (and Coefficient of Determination r²) ........................ 46 II. 6. 1.2. Adjusted Coefficient of Determination ............................................................ 46 II. 6. 1.3. The mean square error “MSE” ......................................................................... 46 II. 6. 1.4. Fisher’s F Test… ............................................................................................. 47 II. 6. 2. Forecasting power .................................................................................................... 47 II. 6. 2.1. Leave-Many-Out Cross-Validation………………………………………………...48 II. 6. 2.2. Leave-One-Out Cross-Validation .......................................................................... 48 II. 6. 2.3. Randomization Test (Y-Randomization Test) for Validation ................................ 48 II. 6. 3. External Predictive Power ....................................................................................... 48 II. 6. 4. Applicability Domain .............................................................................................. 49 REFERENCES……………………………………………………………………………….50 CHAPTER III: QSAR and drug-likeness study for biology activity of 1.4 dihydropyridine III .1. INTRODUCTION………………………………………………………………….55 III .2. MATERIAL AND METHODS…………………………………………………….56 III .3. QSAR STUDY OF 1,4 DIHYDROPYRIDINES DERIVATIVES………………...64 III.3.1. Dataset……………………………………………………………………….64 III.3.2. Drug likeness scoring…………………………………………………………69 III.3.3. Molecular structure and molecular descriptors calculations………………….70 III.3.4. QSAR study………………………………………………………………….71 III .4. RESULTS AND DISCUSSION……………………………………………………71 III.4.1. Molecular structures………………………………………………………….71 III.4.2. Drug likeness screening of 1,4-dihydropyridines derivatives………………...72 III.4.3. Molecular descriptors………………………………………………………...74 III.4.4. Data analysis…………………………………………………………………77 III.4.4.1. Multiple linear regression (MLR)………………………………………….77 III.4.4.2. Artificial neuron network…………………………………………………..80 III .5. CONCLUSION…………………………………………………………………...81 REFERENCES…………………………………………………………………..83 CHAPTER IV: MOLECULAR DOCKING STUDIES OF 1.4 DIHYDROPYRIDINE DERIVATIVES IV .1. INTRODUCTION ................................................................................................. 89 IV .2 . OVERVIEW OF MOLECULAR DOCKING ........................................................ 89 IV .2.1. Various molecular docking techniques .................................................................. 91 IV.2.1.1. Rigid docking ..................................................................................... 91 IV.2.1.2. Semi-flexible docking ........................................................................ 92 IV.2.1.3. Flexible docking… .............................................................................. 92 IV .2.2. Molecular docking algorithms .............................................................. 92 IV .2.3. Scoring function .................................................................................. 93 IV .3- MOLECULAR DOCKING STUDIES ................................................... 93 RESULTS AND DISCUSSION ........................................................................ 94 IV .4. CONCLUSION ..................................................................................................... 98 REFERENCES .................................................................................................... 99 GENERAL CONCLUSION ....................................................................................... 103 |
| Type de document : | Thése doctorat |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/127 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
