| Titre : | Identification of new drugs destined to Alzheimer's patients. |
| Auteurs : | TOUHAMI Moufida, Directeur de thèse ; HADJ MOUSSA Warda Fazya, Auteur |
| Type de document : | texte imprimé |
| Editeur : | UNIVERSITY OF SAIDA - Dr. MOULAY TAHAR Faculty of Science and Technology Department of Materials Science, 2024/2025 |
| Format : | 80 p |
| Accompagnement : | CD |
| Langues: | Anglais |
| Langues originales: | Anglais |
| Catégories : | |
| Mots-clés: | Alzheimer's disorder ; Donepezil-tacrine hybrids ; AChE inhibition ; 3D-QSAR ; molecular docking ; MM-GBSA ; ADME/Tox ; DFT ; electronic properties. |
| Résumé : |
The inhibition of acetylcholinesterase (AChE) continues to be a key therapeutic approach in
Alzheimer's disease treatment. This study employs advanced computational methods to evaluate the AChE-inhibiting potential of hybrid derivatives combining donepezil and tacrine structures. Using robust 3D-QSAR modeling (R² = 0.82, Q² = 0.738), the analysis revealed significant structure-activity relationships (SAR), with steric factors playing a major role (46.05%) in influencing inhibitory potency. These findings facilitated the rational design of new derivatives, using a high-activity reference compound for structural refinement based on contour map analysis. Molecular docking studies identified compound D1 as the most promising candidate, demonstrating strong interactions with key AChE residues (TYR72, ASP74, and TRP286) and an excellent docking score of -11.70 kcal/mol. Further validation through MM-GBSA calculations confirmed its high binding affinity (ΔG ≈ -52.43 kcal/mol) and complex stability. In silico ADME/Tox assessments indicated favorable oral bioavailability, adherence to Lipinski and Veber drug-likeness rules, and minimal toxicity risks. Density functional theory (DFT) analysis (B3LYP/6-311G) revealed a well-balanced HOMO- LUMO energy gap (3.85 eV), suggesting electronic stability and optimal reactivity. Molecular electrostatic potential (MEP) maps and density-of-states analyses further clarified charge distribution and orbital contributions relevant to target binding. Overall, this study highlights the donepezil-tacrine hybrid scaffold as a versatile pharmacophore for AChE inhibition and identifies D1 as a promising anti-Alzheimer's lead compound worthy of further experimental investigation |
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Identification of new drugs destined to Alzheimer's patients. Adobe Acrobat PDF |
