To treat Alzheimer’s Disease (AD), which is the most prevalent form of dementia, cholinesterase enzymes (AChE and BuChE) and amyloid-beta (Aβ) are attractive targets. In this work, different computational approach namely Density Functional Theory (DFT), Molecular Docking, and multi-QSAR modeling were performed on 22 donepezil-based derivatives which were reported as potent dual Aβ and (AChE and BuChE) inhibitors. The molecular geometries of the studied derivatives were carried out using GAUSSIAN 09 software with the level of theory (DFT, 6/31g*). The dual inhibitors adopted minimum energy. The results pointed out the importance of the inhibitors' geometries in enzyme inhibition. The QSAR models elaborated by means of Molecular Operating Environment (MOE) package, showed good statistical values for targets AChE (R²adj = 0.976, q2 = 0.871, RMS = 0.130), BuChE (R²adj = 0.976, q2 = 0.554, RMS = 0.092) and Aβ (R²adj = 0.861, q2 = 0.525, RMS = 0.113). To identify the binding pattern between the ligands and target enzymes, we implemented molecular docking studies for the datasets. The obtained information was related to the essential structural features that were related to the QSAR of the predicted models.
