| Titre : | Une approche computationnelle pour développement d'agents thérapeutiques |
| Auteurs : | Hadjer Khelfaoui, Auteur ; Dalal Harkati, 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, 2022 |
| Format : | 1 vol. (182 p.) / couv. ill. en coul / 30 cm |
| Langues: | Français |
| Langues originales: | Français |
| Résumé : |
Over the last few decades, computer-aided drug design (CADD) has established as a strong tool for developing novel therapeutic compounds. In computer-aided drug design, two methodologies are typically used: structure-based drug design and ligand-based drug design. Molecular docking combined with molecular dynamics is one of the most important tools of drug discovery and drug design, which it used to examine the type of binding between the ligand and its protein enzyme. Global reactivity has important properties, which enable chemists to understand the chemical reactivity and kinetic stability of compounds. The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions confirmed cases and hundreds of thousands death cases around the world so far. In this study, molecular docking and reactivity were applied for eighteen drugs, which are similar in structure to chloroquine and hydroxychloroquine, the potential inhibitors to angiotensinconverting enzyme (ACE2). Those drugs were selected from DrugBank. The reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2 and Crystal structure SARS-CoV-2 spike receptor-binding with ACE2 complex receptor in two active sites to find a ligand, which may inhibit COVID-19. The results obtained from this study showed that Ramipril, Delapril and Lisinopril could bind with ACE2 receptor and Crystal structure SARS-CoV-2 spike receptor-binding with ACE2 complex better than chloroquine and hydroxychloroquine. The tyrosine kinase inhibitors gefitinib and erlotinib activated mutations of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer. Quinazolines and pyridopyrimidines are antibacterial, antifungal, and cancer-fighting compounds. The goal of this study is to look into the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a series of quinazolines and pyrido[3,4-d]pyrimidines as irreversible inhibitors of wild-type (WT) and L858R and T790M EGFR kinase domain mutants, as well as their reactivity, molecular docking, and molecular dynamics simulation. The 27 heterocycles under examination show a wide range of affinities for WT, L858R, and T790M, as well as strong chemical reactivity and kinetic stability. The compounds were found to have high ADMET characteristics, and pyrido[3,4-d]pyrimidines had good reactivity and affinity towards WT, L858R, and T790M mutations. New, powerful, irreversible tyrosine kinase inhibitors have been discovered. Keywords: Covid-19, EGFR, Molecular Docking, Molecular Dyamics, Reactivity, ADMET |
| Sommaire : |
Contents Abstract………….…i Contents………………………….………..iii Contributions of author………………………..………....vii List of abbreviations …………………..…………..ix List of figures…………………..…xiv List of tables……………………….....xviii Preface…………………………1 Chapter I: General concepts I. Foundation of Computer-Aided Drug Design (CADD)..........6 I.1. Overview of CADD.. 6 I.1.1. Drug Design development steps. 6 I.1.2. Drug Discovery Contributing factors. 7 I.1.3. Computer-Aided Drug Design position in the Drug Discovery Pipeline.....8 I.1.4. The Process of Drug Discovery.9 I.1.5. Computer’s roles in Drug Design..9 I.1.6. Computer Simulation for Drug Design...9 I.1.7. Drug Design Theory..... 10 I.1.8. Computers in Drug Design: Success and challenges....12 I.1.9. Chemical structure, representation and analysis...13 I.1.9.1. Library..13 I.1.9.2. Virtual Screening.... 14 I.1.10. Biological structures... 14 I.1.11. Molecular modelling and energy minimization.............15 I.2. Structure-Based Drug Design (SBDD).............16 I.2.1. Molecular Docking...... 16 I.2.1.1. Concept of Molecular Docking..16 I.2.1.2. Virtual Screening..... 17 I.2.2. Molecular Dynamics Simulations.17 I.2.2.1. Principals of Molecular Dynamics Simulations...18 I.2.2.2. Free energy calculation: MM-GBSA....18iv I.3. Ligand-Based Drug Design.....19 I.3.1. Conceptual Density Functional Theory (DFT)......19 I.3.1.1. Fundamental and Computational Aspects of DFT..19 a. The Basics of DFT: The Hohenberg−Kohn Theorems....19 b. DFT as a Tool for Calculating Atomic and Molecular Properties: The Kohn−Sham Equations... 20 I.3.2. Pharmacokinetics Properties....20 I.3.2.1. Computational tools employed in ADMET.......21 II. Virus and Viral Diseases....... 21 II.1. Overview.....21 II.2. Structure of Viruses....... 22 II.3. Life cycle of viruses...23 II.4. The Spike Protein: Key to the Host Cell..........25 II.5. The Two Faces of ACE2: SARS-CoV Receptor and Protector against Lung Damage. 26 II.6. Severe Acute Respiratory Syndrome CoronaVirus-2. 27 II.6.1. SARS-CoV-2 life cycle..... 27 III. Epidermal growth factor receptor tyrosine kinase......28 III.1. EGFR signal pathway and cancers....28 III.2. Mutation status of related genes....30 III.3. Biological and clinical implications of EGFR mutations in lung cancer......32 IV. References..........33 Chapter II: Literature review I. Literature review on covid-19 inhibitors...41 I.1. History...........................41 I.2. Evaluation of drug testing.........42 I.3. Evaluation of natural compounds..... 47 I.4. Syntheses compounds...... 50 II. Literature review on quinazoline and pyridopyrimidine.......52 II.1. Overview......52 II.2. Biological importance of quinazolines.. 53 II.2.1. Quinazolines as anticancer activity 53 II.2.2. Quinazoline as antioxidant activity....... 54v II.2.3. Quinazoline as antibacterial activity.....................54 II.3. Biological importance of Pyridopyrimidine.............. 54 II.3.1. Pyridopyrimidine as anticancer activity........ 54 II.3.2. Pyridopyrimidine as antifungal activity.................56 II.3.3. Pyridopyrimidine as anti-inflammatory activity............................................56 II.3.4. Pyridopyrimidine as anti-diabetes activity................ 57 III. References.............59 Chapter III: Materials and methods I. Overview............. 67 II. Molecule library preparation.......68 II.1. Molecular library preparation for COVID-19 inhibitors...................................... 69 II.2. Molecular library preparation for EGFR inhibitors.............. 72 III. Receptor preparation....75 III.1. Preparation of 1R42 and 6M0J receptors.....75 III.2. Preparation of 1XKK, 2ITV and 5HG5 receptors....... 77 IV. Global reactivity descriptors....79 V. Molecular Docking.....................80 VI. Molecular Dynamics Simulations...82 VII. Computational Pharmacokinetics.... 82 VIII. References...........84 Chapter IV: Results and discussion I. Results and discussion on approved drugs library targeting ACE2 and SARS-CoV-2 binding with ACE2....................89 I.1. Reactivity.............. 89 I.1.1. Results..........89 I.1.2. Discussion.........91 I.2. Molecular Docking........ 91 I.2.1. Results.......91 I.2.1.1. The binding affinities of the drugs into ACE2 active sites......91 I.2.1.2. The binding affinities of the drugs into SARS-CoV-2 spike receptorbinding with ACE2 complex active sites.103 I.2.2. Discussion........119 I.3. Molecular Dynamics simulations..121vi I.3.1. Results..........121 I.3.2. Discussion...127 II. Result and discussion of Various Quinazolines and Pyridopyrimidines as Inhibitors of the Epidermal Growth Factor Receptor.....128 II.1. Reactivity........ 128 II.1.1. Results...........128 II.1.2. Discussion...........131 II.2. Molecular Docking.... 131 II.2.1. Results.....131 II.2.1.1. The binding affinities of the ligands into wild-type.............131 II.2.1.2. The binding affinities of the ligands into L858R mutation..................138 II.2.1.3. The binding affinities of the ligands into T790M mutation............. 143 II.2.2. Discussion..147 II.3. Molecular Dynamics simulation 148 II.3.1. Results....148 II.3.2. Discussion...........151 II.4. Pharmacokinetics properties...... 151 II.4.1. Results and discussion............151 III. References......155 Conclusion………………………………………………………………………………..157 Appendix…………………………………………………………………………………160 |
| Type de document : | Thése doctorat |
| En ligne : | http://thesis.univ-biskra.dz/id/eprint/5741 |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/93 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
