Huperzine A with Idebenone: Using Molecular Docking to analyze a potential Combination Therapy for Alzheimer’s Disease by Inhibition of the Acetylcholinesterase Enzyme

Those suffering from Alzheimer’s disease (AD) have low concentrations of Acetylcholine (ACh), a neurotransmitter involved in learning, memory, and muscle contraction. Acetylcholinesterase (AChE), a cholinergic type enzyme, plays a crucial role in concluding neurotransmission and degrading ACh. The accumulation of the AChE protein in AD patients results in decreased levels of ACh, and contributes to the buildup of amyloid-beta (Aβ) plaques that are crucial in the onset of AD. This study aims to examine how Idebenone could work as a potential inhibitor in addition to Huperzine A for AChE inhibition as a possible combination therapy for Alzheimer's Disease. Structure files of the inhibitors and AChE (PDB ID: 1VOT) were manipulated using PyMOL, GNINA, and Google Colab for molecular visualization and docking to find bond energies and possible ligand-protein interactions. The results confirmed that Idebenone has a significant binding affinity, though relatively lower than Huperzine A and in a different location, to be a useful component in this combination therapy due to its variety of interactions within AChE’s binding cavity including hydrogen bonds, hydrophobic and aromatic interactions. Huperzine A, with its stronger binding affinity, also exhibited positive interactions with amino acids surrounding the binding cavity of AChE, including hydrophobic and aromatic interactions. Most notably, the placement of each of these molecules did not significantly impact one another. Therefore, we can conclude that when used in conjunction, the two inhibitors target distinct locations in the wide binding pocket of AChE, and complement one another in the areas each can not cover alone. Their neuroprotective qualities also aid in the treatment of the disease. Future research could explore longer inhibitors to optimize binding within AChE's binding cavity and test the efficacy of this combination therapy on other neurodegenerative diseases involving cholinergic dysfunction.