Tacrine-Flavonoid Quercetin Hybride as a MTDL Ligand against Alzheimer’s Disease with Metal Chelating and AChE, BChE, AChE-induced Aβ Aggregation Inhibition Properties: A Computational Study

AChE is an enzyme that is predominate in a healthy brain, while BChE is considered to play a minor role in regulating the levels of ACh (memory molecule) in the brain. In addition to setting the ACh level, these two enzymes also facilitate Aβ aggregation by forming stable complexes and participate in the abnormal phosphorylation of the tau protein, which also contribute to the development of Alzheimer’s disease (AD). Trace elements including Zn2+, Cu2+, and Fe2+ are found in the brain plaques of Alzheimer’s patients. This study employed tacrine as an efficient inhibitor of cholinesterase and quercetin as a natural metal chelating agent to design a new multi-target-directed ligand, which has been named Tac-Quer. The chelating properties of this ligand have been studied by quantum calculations. The Tac-Quer/Metal binding energies for Zn2+, Cu2+, and Fe2+ are -939. 08, -917.62, and - 694.103 kcal.mol-1, respectively. The cholinesterase enzyme inhibitory activity of the Tac-Quer ligand has been evaluated via molecular dynamic simulations. The free energies for the AChE/Tac-Quer and BChE/Tac-Quer complexes are -17.17 and -29.16 kcal.mol-1, respectively. Based on the results of this investigation, Tac-Quer is introduced as a potent multi-target-directed ligand that can be recognized as a promising treatment for AD.