In silico and in vitro studies confirm Ondansetron as a novel acetylcholinesterase and butyrylcholinesterase inhibitor

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is growing rapidly among the elderly population around the world. Studies show that a lack of acetylcholine and butyrylcholine due to the overexpression of enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) may lead to reduced communication between neuron cells. As a result, seeking novel inhibitors targeting these enzymes might be vital for the future treatment of AD. Ondansetron is used to prevent nausea and vomiting caused by chemotherapy or radiation treatments and is herein shown to be a potent inhibitor of cholinesterase. Comparison is made between Ondansetron and FDA-approved cholinesterase inhibitors Rivastigmine and Tacrine. Molecular docking demonstrates that interactions between the studied ligand and aromatic residues in the peripheral region of the active site are important in binding. Molecular dynamics simulations and binding pose metadynamics show that Ondansetron is highly potent against both enzymes and far better than Rivastigmine. Inhibitor activities evaluated by in vitro studies confirm that the drug inhibits AChE and BChE by non-competitive and mixed inhibition, respectively, with IC50 values 33 mu M (AChE) and 2.5 mu M (BChE). Based on the findings, we propose that Ondansetron may have therapeutic applications in inhibiting cholinesterase, especially for BChE.

Automated summary

Alzheimer's disease is a progressive neurodegenerative disorder that affects the elderly population worldwide. Deficiency of acetylcholine and butyrylcholine due to the overexpression of AChE and BChE enzymes can lead to impaired neuron communication. In this study, Ondansetron, a drug used for preventing chemotherapy-induced nausea and vomiting, is found to be a potent inhibitor of cholinesterase enzymes. Molecular docking and dynamics simulations demonstrate its higher efficacy compared to Rivastigmine and Tacrine. In vitro studies confirm its inhibitory activity on AChE and BChE, making it a potential therapeutic option for AD treatment.