| Titre : | Application of drug design strategies to predict new bioactive molecules |
| Auteurs : | Lotfi Bourougaa, Auteur ; Ouassaf Mebareka, Auteur |
| 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, 2024 |
| Format : | 1VOL.(131p) / ill.couv.ill.en coul / 30cm |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Mots-clés: | Key Word: Influenza, Neuraminidase, Pharmacophore, Molecular docking, Fragment-based drug design, Breed-Based De Novo Hybridization, 3D-QSAR, CoMFA, Gromacs, MM-PBSA. |
| Résumé : |
Influenza is a pulmonary infection triggered by a virus that produces fever. Periodic epidemics can be fatal. Antiviral therapy shortens the length of sickness by around one day and will need to be explored especially for high-risk individuals. This work was focused on discovering and developing novel and effective anti-influenza medicines. Neuraminidase was chosen as the major target due to its critical activity and importance in the life of the influenza virus. Several compounds were created in the first stage using pharmacophore modeling, fragment-based drug design, BreedBased De Novo Hybridization and 3D-QSAR (CoMFA model). The docking modeling data reveal that all of the designed compounds bind well to the Neuraminidase receptor in comparison with the clinical blockers. Moreover, each compound's pharmacokinetic profile has been verified, particularly its aqueous solubility, permeability, and bioavailability. The potential toxicity of each developed molecule was assessed using the ProTox II platform and the VEGA QSAR package. The atomic mobility of the generated complexes between the proposed compounds and Neuraminidase receptor was examined using molecular dynamics simulations performed for 100 ns via Gromacs package. All of the data show that the formed complexes (designed molecules_Neuraminidase) have high biomolecular stability. Finally, the results of molecular docking were confirmed by MM-BPSA calculations. |
| Sommaire : |
I.1 Introduction.......6 I.2 Neuraminidase Morphology...............................7 I.2.1 Transmembrane zone..................................7 I.2.2 Cytoplasmic tail ambit...................................8 I.2.3 Catalytic head...........................................9 I.2.4 Stalk......................................................9 I.3 Mechanism of Action of NAIs........................................................10 I.4 Safety of Neuraminidase Inhibitors............................... I.4.1 Zanamivir.........................................11 I.4.2 Oseltamivir...............................................11 I.5 Neuraminidase Mutations Linked to NAI Resistance..............................................................13 I.6 Creating Neuraminidase-Inhibitors in Future Years.....................14 I.7 References............................................................16 Chapter II: Drug Design Strategies II.1 Introduction...........................................21 II.2 Computer-Aided Drug Design Strategies.......................21 II.2.1 Structure-based drug design (SBDD)..................................................22 II.2.2 Ligand-based (LBDD).............................................23 II.2.2.1 Quantitative structure–activity relationship (QSAR).........23 II.2.2.2 Pharmacophore modeling.................................................24 II.2.2.3 BREED Based De Novo Hybridization strategy...............25 II.3 ADME and Drug Likeness..................................................26 II.3.1 Solubility...........................................................27 II.3.2 Lipophilicity....................................................27 II.4 In Silico Toxicity Prediction............................................28 II.5 Molecular Dynamics Simulation (MDS)....................................29 II.6 References.................................................31 III.1 Introduction....................................................35 III.2 Materials and Methods..............................................36 III.2.1 Ligand preparation........................................36 III.2.2 Protein preparation...........................................37 III.2.3 Generation of pharmacophore model................................................................37 III.2.4 Construction of the 3D-QSAR model...............................................................37 III.2.5 Model validation................................................37 III.2.6 Virtual screening and docking study.................................................................38 III.2.7 ADMET study......................................................38 III.2.8 Molecular dynamics simulation........................................................................38 III.2.9 Method of MMPBSA analysis..........................................................................39 III.3 Results and Discussion...........................................39 III.3.1 Pharmacophore and 3D-QSAR models............................................................39 III.3.2 Model validation.....................................40 III.3.3 3D-QSAR contour maps analysis.....................................................................41 III.3.4 Virtual screening and docking studies..............................................................42 III.3.5 Prediction of .........toxicity..............................46 III.3.7 Molecular dynamics study........................47 III.3.8 MMPBSA analysis......................50 III.4 Conclusion....................................................................52 III.5 References.......................................................................53 Chapter IV: Discovery of Novel Potent Drugs for Influenza by Inhibiting the Vital Function of Neuraminidase via Fragment-Based Drug Design (FBDD) and Molecular Dynamics Simulation Strategies IV.1 Introduction...................56 IV.2 Computational Methods...58 IV.2.1 Protein and fragments preparation.............................58 IV.2.2 Fragment linking and molecular docking studies............................................58 IV.2.3 ADMET prediction..............................59 IV.2.4 Molecular dynamic simulation..................................59 IV.2.5 MM-PBSA calculations.........................60 IV.2.6 Reaction based enumeration...................60 IV.3 Results and Discussion.................................................60 IV.3.1 Fragment-based drug design and molecular docking......................................60 IV.3.2 ADMET and bioavailability....................................66 IV.3.3 Molecular dynamic simulation (MDS)............................................................68 IV.3.3.1 RMSD and RMSF analysis..................................................................68 IV.3.3.2 Radius of gyration (Rg) analysis.........................................................70 IV.3.3.3 Hydrogen bonds analysis.....................................................................71 IV.3.3.4 Solvent accessible surface area (SASA) analysis................................71 IV.3.4 MM-PBSA analysis...........................................72 IV.3.5 Reaction based enumeration.................................74 IV.4 Conclusion......................................................75 IV.5 Re.....................................................77 Chapter V: Pharmacoinformatics and Breed-Based De Novo Hybridization Studies to Develop New Neuraminidase Inhibitors as Potential Anti-Influenza Agents V.1 Introduction............................................................80 V.2 Materials and Methods....................................................81 V.2.1. Breed De Novo hybridization approach.....................................81 V.2.2 Molecular docking study.......................................................83 V.2.3 ADME-Tox prediction.........................................................83 V.2.4 Molecular dynamic simulation.........................................83 V.2.5 Binding free energy..........................................................84 V.2.6 Reaction-based enumeration..............................84 V.3 Result...........................................................85 V.3.1 Breed-based De Novo and molecular docking approaches...............................85 V.3.2 ADMET prediction.....................................................90 V.3.3 Study of molecular dynamics................................................91 V.3.3.1 RMSD and RMSF analysis.........................................91 V.3.3.2 Radius of gyration (Rg)..............................................94 V.3.3.3 Hydrogen binding analysis.................................................................94 V.3.3.4 Solvent-accessible Surface area (SASA).....................95 V.3.4 MM-PBSA Analysis.......................................................96 V.3.5 Reaction-Based Enumeration............................................98 V.4 Discussion...........................................................102 V.5 Conclusion.....................103 V.6 References.......................105 VI.1 Introduction....................109 VI.2 Materials and Methods....111 VI.2.1 Experimental databases...............111 VI.2.2 Structure preparation and alignment....................................111 VI.2.3 Generation of 3D-QSAR by CoMFA...................111 VI.2.4 PLS analysis and validations.....................112 VI.2.5 Molecular docking..............................113 VI.1.6 Prediction of ADMET properties...................114 VI.3 Results and Discussions.............. VI.3.1 Molecular alignment of dataset.................................114 VI.3.2 3D-QSAR model and validations..........................................115 VI.3.3 CoMFA contour cap..............................................................116 VI.3.4 Design for new neuraminidase inhibitors...........................117 VI.3.5 Molecular docking...............................121 VI.3.6 ADMET and bioavailability prediction........................... Conclusion..................... General Conclusion..............131 |
| Type de document : | Thése doctorat |
| En ligne : | http://thesis.univ-biskra.dz/id/eprint/6820 |
Disponibilité (1)
| Cote | Support | Localisation | Statut |
|---|---|---|---|
| TCH/122 | Théses de doctorat | bibliothèque sciences exactes | Consultable |
