Acetylcholinesterase with Bound Aricept (Donepezil)
This Jmol Exploration was created using the Jmol Exploration Webpage Creator from the MSOE Center for BioMolecular Modeling.
Alzheimer's disease (AD), the most common cause of dementia, is a progressive, incurable disease that usually affects adults over the age of 65. There is no known cause for this disease, and as a result, there is not an available cure. The only way to treat AD is to treat the symptoms. According to the American Academy of Neurology, cholinesterase inhibitor therapies should be used to manage the symptoms of dementia in patients with mild to moderate AD.
A 75-year-old female presented to Wal-Mart pharmacy with a new prescription for oxybutynin 5 mg daily for the treatment of an overactive bladder. The pharmacist noticed that this patient was also on donepezil (Aricept') 10 mg daily for the treatment of dementia from AD. Since the addition of oxybutynin, an anticholinergic medication, can reduce the effectiveness of donepezil, the pharmacist informed the patient of the potential interaction. After talking with the patient, the pharmacist called the physician to inform him of the interaction. The physician preferred to continue with the planned medications of donepezil and oxybutynin. The pharmacist recommended the patient follow up with her physician to monitor for signs and symptoms of efficacy and increase or return of symptoms of AD.
Acetylcholine (ACh) is a major neurotransmitter involved in the pathophysiology of Alzheimer's disease (AD). A decrease in levels of ACh in the brain is thought to be involved in some of the cognitive symptoms of AD, specifically memory loss. There are currently only a few drugs on the market which are approved to treat Alzheimer's disease, one of them being donepezil. Donepezil is a reversible acetylcholinesterase (AChE) inhibitor, which binds to the active site of the enzyme that degrades ACh and thus prevents the hydrolysis of it. This results in an increased concentration of ACh in the synapses available for neurotransmission. It is generally accepted that therapeutic effects are related to cholinergic stimulation in the brain. The alpha-7 nicotinic receptors are especially important in the cerebral cortex and hippocampus. These areas aid in the regulation of cognitive and behavioral processes. While this drug can improve the cognitive symptoms of AD, it does not treat the underlying cause for the disease.
Clinical testing for donepezil's potential role in AD therapeutics began in 1990 under the name E2020. First, blind screenings of compounds with similar structures that have inhibitory effects on acetylcholinesterase were performed and a benzylpiperidine compound was discovered. This compound was subjected to optimization, where it was found that methyl substitution on the amide nitrogen of the benzamide created enhanced activity of the compound. Further investigation of this compound using quantitative structure-activity relationship (QSAR) showed the intrinsic activity of the cis isomer to be higher than the trans isomer. Upon further optimization, it was found that there were three main structural characteristics necessary for a compound to have the highest activity: cis conformation, bulky groups at the para position of the benzamide, and carbonyl oxygen of the amide (proton acceptor for an intermolecular hydrogen bond). Different compounds with the three characteristics were made, one of which was E2020. Docking simulations were used to demonstrate the high activity of E2020. Docking was performed on the atomic coordinates of E2020 to show that E2020 analogues can inhibit the hydrolytic reaction of acetylcholinesterase. From this, donepezil was discovered and further developed by the Japanese company, EISAI INC.
Donepezil has greater specificity for the centrally-acting AChE enzymes, resulting in fewer adverse side effects than those previously on the market. The design of the drug produced high affinity and selectivity for the enzyme AChE, but not for butyrycholinesterase (BChE). The central nervous system selectivity is highlighted by the lack of activity in peripheral tissue such as cardiac tissue or gut smooth muscle. It is proposed that when a drug binds both AChE and BChE, the side effects are more severe.
Donepezil also displays a longer duration of action, meaning that it can be dosed once daily. The 5 mg and 10 mg oral tablets were approved by the FDA in November, 1996 followed by the oral solution and oral disintegrating tablets in October, 2004. Finally, the 23 mg oral tablets were approved in July, 2010. Generics were approved beginning in January of 2007 with the many more coming to market in May, 2011.
Please click on the button below to view the protein with bound drug.
Acetylcholinesterase with Bound Aricept (Donepezil)Click on the buttons below to view the secondary structure of acetylcholinesterase.
Secondary Structure of the ProteinDonepezil is an N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitor that has three distinctive portions of the molecule. The structure is made up of a dimethoxyindanone portion, a piperidine portion, and a benzyl ring. All three segments of the molecule have specific interactions within the binding site of AChE. The benzyl ring is involved in a parallel pi-pi stacking interaction with the Trp84. The parallel orientation of the benzyl moiety to Trp84 is clearly visible. There are also water molecules at this end that aid in stabilizing the compound in this section of the binding pocket. It is worth noting that donepezil does not interact with the catalytic triad (the portion that would hydrolyze ACh) and therefore is able to bind to both the active and inactive conformations of the enzyme.
In the middle segment of donepezil, there is a piperidine ring with a charged nitrogen that interacts with Phe330. This nitrogen also forms a hydrogen bond with water molecule WAT 1159. These interactions further stabilize the molecule in the binding site. At the other end of the molecule, another pi-pi interaction happens between the dimethoxyindanone ring and the ring of Trp279. Specific van der Waals interactions with nearby side chains also help favor the binding of donepezil. There are also some important interactions with water molecules at this end that help stabilize the molecule.
Click on the button below to see the three distinct chemical regions of Aricept. The dimethoxyinandone region flashes purple, the piperidine region flashes in green, and the benzyl region flashes in blue. Also, compare the 3-D structure with the 2-D image (above). Are there any key differences?"
Aricept (Donepezil)Click on the button below to see the hydrogens and different bonds within the Aricept molecule.
Note: click 'OK' on the message that pops up.
What are the three distinct chemical regions of this drug?
Click on the button below to see Aricept in the binding pocket. The drug flashes lime green.
Aricept (Donepezil) in the Binding PocketImportant sidechains flash in cyan in the next button (below).
Binding Pocket OnlyThese next few buttons show specific interactions between Aricept, sidechains, and water molecules.
Trp84 interacting with the benzyl ringAs previously mentioned, acetylcholine (ACh) is broken down by acetylcholinesterase (AChE) found in the neuronal synapse. Donepezil inhibits the AChE, leading to more available ACh in the central nervous system. This ACh is then available to increase binding on the nicotinic acetylcholine receptors in the brain, which reduces the cognitive symptoms experienced in Alzheimer's Disease (AD). Oxybutynin is an anticholinergic drug which antagonizes ACh at the muscarinic cholinergic receptors throughout the body. While these receptors are not identical to the nicotinic ACh receptors in the brain, there are structural similarities. Oxybutynin may have some off-target effects by binding to the nicotinic receptors and thus preventing the increased ACh from binding. Overall, this would result in the decreased efficacy of donepezil and may potentially require a dosage adjustment. Donepezil has numerous other drug-drug interactions with other cholinesterase inhibitors, CYP-450 inhibitors, CYP-450 inducers, aspirin, NSAIDs, and anticholinergics. In this particular case, the patient is on the anticholinergic, oxybutynin, a common medication used to treat overactive bladder. If the patient were to take oxybutynin in conjunction with donepezil, it is possible that she would experience an increase in symptoms from AD due to decreased efficacy of donepezil. A two-year prospective cohort study comparing bladder anticholinergics and cholinesterase inhibitors found the functional rate of the participants with AD declined 50% faster when bladder anticholinergics were used with a cholinesterase inhibitor.
After further review, the Wal-Mart pharmacist consulted the patient on the use of donepezil and oxybutynin together. She may experience some of the original symptoms that she experienced before starting donepezil. To monitor these symptoms more closely she should check in with her physician to monitor cognitive abilities and activities of daily living. If these symptoms arise the donepezil dose could potentially be increased up to 23 mg daily, based on a randomized double blind study. There is a potential that the dose increase could cause side effects or potential toxicity. Some of these side effects include nausea, vomiting, diarrhea, muscle cramps, and abnormal dreams. The patient was told that if these symptoms occur, to talk to a health care professional. These medications can be used concurrently with proper monitoring of side effects and follow up.
These Jmol buttons explore the interactions and the binding pocket. First, you'll see the 'surface' around Aricept. The color variations on that surface show the neighboring interactions (red = close contact, blue = not as close).
Second, you'll see the surface of the entire protein around Aricept; specifically, you are looking at the visualization of the van der Waals interactions of the protein. The last button shows the same van der Waals interactions, but only within 5 Å of Aricept.