Mechanistic Insights into Tacrine Binding to Acetylcholinesterase in Alzheimer’s Disease from Molecular Docking and Molecular Dynamics Simulations

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory loss and cognitive decline. Acetylcholinesterase (AChE) is an important therapeutic target in the treatment of AD, and tacrine is one of the earliest drugs used as an AChE inhibitor. In the present study, computational methods were used to investigate interaction of tacrine with acetylcholinesterase (PDB ID: 1EVE). The tacrine molecule (1,2,3,4-tetrahydroacridin-9-amine; C 13 H 14 N 2 ) was optimized using Gaussian software, followed by molecular docking to study its binding behavior within the active site of the protein. Docking analysis showed that tacrine binds effectively with acetylcholinesterase, with a binding energy of − 7.17 kcal/mol and the formation of hydrogen bond interactions, indicating favorable binding within the enzyme cavity. To further examine the stability of the complex, the best-docked structure was subjected to a 100 ns molecular dynamics (MD) simulation using GROMACS. The RMSD, RMSF, and radius of gyration analyses indicated that the protein remained structurally stable and compact throughout the simulation, while the ligand stayed firmly bound within the active site. Interaction analysis revealed that the complex is mainly stabilized by strong π–π stacking interactions with important aromatic residues such as Trp84, Tyr121, Tyr334, and Phe330. Hydrophobic interactions and transient hydrogen bonds also contributed to the stability of the ligand–protein complex. The study shows that tacrine forms a stable interaction with acetylcholinesterase and highlights the importance of aromatic interactions in ligand binding. These findings may help in the future design and optimization of improved acetylcholinesterase inhibitors for Alzheimer’s disease treatment.