Integrated In Silico Quantum Chemical and Molecular Docking Analysis for the Identification of Natural Compounds Targeting the Pathological Tau Protein Associated with Alzheimer's Disease

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and irreversible neuronal loss. Hyperphosphorylation and aggregation of the Tau protein are key pathological events that promote neurofibrillary tangle formation and contribute to disease progression. Owing to the limited efficacy of current therapeutic strategies, natural products from Saharan medicinal plants have attracted increasing attention as potential sources of neuroprotective agents. This study aimed to identify promising Tau inhibitors through an integrated in silico approach combining quantum chemical calculations, molecular docking, and molecular dynamics simulations.

Methods: Selected phytochemicals were geometrically optimized using Density Functional Theory (DFT) . Electronic descriptors, global electrophilicity index, and molecular electrostatic potential, were calculated to evaluate molecular reactivity. The optimized compounds were docked into the binding site of the phosphorylated Tau protein to assess binding affinity and interaction patterns. The most promising complexes were subsequently subjected to molecular dynamics simulations to investigate their structural stability under physiological conditions.

Results: Several phytochemicals exhibited favorable electronic properties and strong binding affinities toward the Tau protein. The best-performing compounds established multiple hydrogen bonds and hydrophobic interactions with key amino acid residues, indicating high binding specificity. Molecular dynamics simulations confirmed the stability of the selected ligand–protein complexes throughout the simulation, demonstrating persistent interactions and minimal structural deviations.

Conclusions: The integrated computational workflow identified several Saharan plant-derived metabolites as promising Tau-targeting candidates for Alzheimer's disease. These findings provide a robust theoretical basis for future experimental validation and support the development of natural-product-based therapeutics for Tau-associated neurodegenerative disorders.