| Titre : | Computational Approaches to Understanding the Structural Features of Small Molecules of Biological Interest |
| Auteurs : | Narimene Chahbaoui, Auteur ; Saida Khamouli , 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.(124.p) / ill.couv.ill.en coul / 30cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Résumé : |
Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and lethal forms of cancer, characterized by a dismal prognosis largely due to late-stage diagnosis and the inadequate effectiveness of current treatment options. Recognizing the urgent need for innovative therapies, this thesis adopts a dual approach, exploring both direct and indirect inhibition mechanisms to tackle the challenges associated with PDAC treatment. By integrating computer-aided drug design with the chemical diversity of natural products, novel small-molecule inhibitors with potential efficacy against PDAC were identified. Divided into two main parts, the study begins with an exploration of curcumin derivatives as potential inhibitors of PI3Kα. Through virtual screening that employed pharmacophore modeling and molecular docking, two promising compounds were identified: CID154728220 and CID156189304. Both compounds exhibited favorable pharmacokinetic profiles, and subsequent MD simulations confirmed their structural stability, making them strong candidates for further preclinical evaluation. The second part utilized a fragment-based drug discovery approach to directly target KRAS G12D. This strategy led to the discovery of two novel compounds, Hit1 and Hit2, which demonstrated higher binding affinity compared to the reference inhibitor MRTX1133, as validated by IFD and MM-GBSA analysis. Notably, Hit2 exhibited the most favorable balance of pharmacokinetic properties, safety, and drug-likeness, positioning it as a promising candidate for further development. This thesis represents a significant advancement in cancer research, providing a foundation for the development of novel therapeutic strategies in the treatment of pancreatic cancer. Keywords: Pancreatic cancer, virtual screening, natural pr |
| Sommaire : |
I.1 Introduction .................................................................................................................. 6 I.2 Pancreatic cancer .......................................................................................................... 7 I.2.1 Pancreas anatomy and function ................................................................. 7 I.2.2 Clinical aspects of pancreatic cancer ......................................................... 8 I.2.3 Global trends and risk factors in pancreatic cancer ................................... 9 I.2.4 Current management of pancreatic cancer .............................................. 11 I.2.5 Genetic mutations in PDAC .................................................................... 11 I.2.5.1 Oncogenic KRAS mutations .............................................................. 13 I.2.5.2 RAS proteins ....................................................................................... 14 I.2.6 Targeting KRAS ...................................................................................... 15 I.2.6.1 Directly ............................................................................................... 15 I.2.6.2 Indirectly ............................................................................................. 15 I.2.7 PI3K/AKT/mTOR pathway ..................................................................... 17 I.2.7.1 PI3Kα as a potential target for PDAC treatment ................................ 19 I.3 Natural products in drug design ................................................................................. 20 I.3.1 From historical milestones to modern rediscovery .................................. 20 I.3.2 Curcumin : The Indian solid gold ............................................................ 22 I.3.2.1 Occurrence and physicochemical properties ...................................... 22 I.3.2.2 Curcumin in cancer treatment ............................................................. 23 I.3.2.3 Curcumin bioavailability .................................................................... 26 References ........................................................................................................................... 29 II.1 Introduction ............................................................................................................... 38 II.2 Virtual screening ....................................................................................................... 39 II.2.1 Ligand-based virtual screening .............................................................. 39 II.2.1.1 Ligand-based pharmacophore modeling ........................................... 39 II.2.1.2 3D-QSAR .......................................................................................... 44 II.2.1.3 Similarity searching ........................................................................... 49 II.2.1.4 ADMET ............................................................................................. 49 II.2.2 Structure-based virtual screening ........................................................... 49 II.2.2.1 Molecular docking ............................................................................. 49 II.2.2.2 Fragment-based drug discovery ........................................................ 54 II.3 Molecular dynamics simulations .............................................................................. 56 II.3.1 Foundations of molecular dynamics ...................................................... 56 II.3.2 Periodic boundary conditions ................................................................. 58 II.3.3 Statistical ensemble ................................................................................ 59 II.3.4 Main steps of a molecular dynamics simulation .................................... 60 II.4 Binding energy .......................................................................................................... 61 References ........................................................................................................................... 63 Chapter III: Application 1 – Comprehensive Computational Strategies to Identify Novel Curcumin Derivatives Against Pancreatic Cancer III.1 Introduction ............................................................................................................. 70 III.2 Material and methods .............................................................................................. 71 III.2.1 Dataset preparation ............................................................................... 71 III.2.2 Pharmacophore and 3D-QSAR modeling ............................................. 71 III.2.3 Database preparation and pharmacophore-based screening ................. 72 III.2.4 Protein preparation ................................................................................ 73 III.2.5 Grid generation and structure-based virtual screening ......................... 73 III.2.6 ADMET prediction ............................................................................... 74 III.2.7 Molecular dynamics simulations .......................................................... 74 III.3 Results and discussion ............................................................................................. 74 III.3.1 Pharmacophore 3D-QSAR modeling ................................................... 74 III.3.2 Model validation ................................................................................... 83 III.3.2.1 Enrichment study ............................................................................. 83 III.3.2.2 External validation ........................................................................... 84 III.3.2.3 Y-randomization test ........................................................................ 85 III.3.3 3D-QSAR contour map analysis ........................................................... 86 III.3.4 Pharmacophore-based virtual screening ............................................... 88 III.3.5 Molecular docking-based screening ..................................................... 88 III.3.6 ADMET analysis .................................................................................. 93 III.3.7 Molecular dynamics simulations .......................................................... 97 III.4 Conclusion ............................................................................................................. 102 References ......................................................................................................................... 104 Chapter IV: Application 2 – Targeting KRAS G12D Using Fragment-Based Drug Discovery IV.1 Introduction ........................................................................................................... 107 IV.2 Material and methods ............................................................................................ 108 IV.2.1 Protein preparation .............................................................................. 108 IV.2.2 Fragment libraries preparation ............................................................ 108 IV.2.3 Fragment screening ............................................................................. 109 IV.2.4 Fragment linking ................................................................................. 109 IV.2.5 Molecular docking .............................................................................. 109 IV.2.6 Induced Fit Docking and MM-GBSA calculations ............................ 110 IV.2.7 ADMET prediction ............................................................................. 110 IV.3 Results and discussion ........................................................................................... 110 IV.3.1 Fragments screening and linking ........................................................ 110 IV.3.2 Analysis and visualization of molecular docking results ................... 111 IV.3.3 IFD and MM-GBSA analysis ............................................................. 113 IV.3.4 ADMET analysis ................................................................................ 116 IV.4 Conclusion ............................................................................................................. 119 References ......................................................................................................................... 120 General Conclusion ......................................................................................................... 122 Appendix .......................................................................................................................... 124 |
| Type de document : | Thése doctorat |
| En ligne : | http://thesis.univ-biskra.dz/id/eprint/6829 |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/124 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
