Probing the Binding Ability of Quinoxaline Derivatives towards Tau Protein: A Theoretical Insight

The aggregation of tau proteins is a characteristic feature of several neurodegenerative disorders, including Alzheimer's disease. In this study, a computational approach was employed to identify and evaluate potential small-molecule ligands targeting the Tau protein. Ten ligands were initially screened using molecular docking with AutoDock 4.2, revealing Ligand 10 as the most promising candidate, exhibiting the strongest binding energy (–7.39 kcal/mol), multiple hydrogen bonds, and interactions with eight Tau residues. Key amino acids such as Asn359, Gly367, and Phe346 emerged as frequent binding sites, indicating potential hotspots within the Tau binding region (residues 320–370). Additionally, Molecular Electrostatic Potential (MESP) analysis on optimized ligand structures identified the most reactive regions, primarily around carbonyl and nitrogen-containing functional groups. To gain deeper insights into the electronic nature of ligand–Tau interactions, DFT calculations were performed using the wB97XD/6-311 + G(d,p) method on model Tau–ligand complexes. The results supported the docking findings, with Ligand 10 showing the most favorable interaction energy (–49.9 kcal/mol). Together, these results highlight Ligands 10, 2, and 9 as promising leads for further experimental validation and optimization. This integrated computational framework provides valuable direction for the rational design of Tau-targeted therapeutics for neurodegenerative disorders. The in silico prediction of ADME properties also indicated that the proposed ligand molecules possess notable drug-likeness characteristics.