
Aricept, an acetylcholine esterase inhibitor used to treat Alzheimer’s disease and other conditions that benefit from enhanced accumulation of acetylcholine, is an example of a molecule with multiple hydrophobic rings that binds to an enzyme.
I want to discuss aricept as an arbitrary example that I just looked up to illustrate the lack of specificity of statins that I will characterize in another article as little more than molecular skeleton keys that work on many different enzymes.


Typical low energy, noncovalent bonds in water, such as ionic bonds are readily broken by the thermal, kinetic energy of water -- they get knocked apart. The energy of these bonds is only 1-2 kcal/mol. In contrast, the stacked hydrophobic rings are quite stable, because it takes ten times the energy to separate them, 20 kcal/mol.
Aricept binds t


The aricept is bound to yellow tryptophans at both ends and the middle ring is bound to the hydrophobic ring of orange tyrosine. The geometry of the interaction is important, but many other molecules with fewer rings would also bind to the same hydrophobic,

Statins were found by testing fungal extracts for molecules that would inhibit an enzyme (HMG-CoA reductase) in lipid metabolism. The normal lipid substrates for that enzyme would also be expected to bind to the surface of rings in the acetylcholine esterase enzyme. In fact, I would expect to find molecules from fungal extracts that would inhibit acetylcholine esterase.
I demonstrated the nonspecificity of all of these binding events with the aromatic rings in the ac

I am setting the stage for a discussion in a future article of what kind of activities would be expected from fungal molecules that were identified by the statin screening. It is not surprising that the statins have many activities other than reducing LDL. The only statins that are effective in treating cardiovascular disease are those that also lower inflammation. It is also not surprising that statins have many side-effects.
20 comments:
This is all highly relevant to my mum, who's only just re-started taking Aricept after 8 days of not taking it.
I found an acetylcholinesterase inhibitor called Huperzine A. 50mcg/day of Huperzine A is supposedly an effective dose, compared to 5mg/day for Aricept. Huperzine A is ~£13 for 60 days supply compared to Aricept which is ~£60 for 28 days supply. Have you studied Huperzine A?
Nigel,
My article was a response to your note about your mother's use of Aricept. I just used it as an instant example to demonstrate that any randomly chosen molecule will show some binding to dozens of common enzymes. I just looked up Aricept in the structure database and since someone paid to show that it is effective in blocking acetylcholine esterase, the structure was there.
Huperzine A shows that there is heavy selection pressure on plants to produce molecules that are highly effective in binding to animal enzymes. Each drug has hundreds of interactions that differ for each person and change with physiology. It is all a wicked empirical game.
I can't claim expertise in predicting outcomes. Was the sudden withdrawal of Aricept and the resulting suite of changed interactions the problem? Changing to Huperzine would provide a new suite of interactions. Good or bad? It is all dependent on too many variables. My prejudice is to get her back into as normal a routine as possible and try to reinforce the normal behaviors.
I just hope that your mum's condition improves.
There were two things going on at the same time. The UTI caused initial increasing confusion resulting in mum discontinuing Aricept which caused additional increasing confusion until she collapsed and couldn't get up.
I'm hoping that correcting both of the above problems will restore her mental faculties to close to their previous level. Correcting the UTI alone has not restored much of her mental faculties and she was fairly unresponsive on Wednesday. While mum is in hospital, I am unable to give her Vit D3, curcumin, berberine or lots of smoked salmon, which may hinder her progress.
As it's difficult to tweak the dose of Aricept (it's only available as 5mg & 10mg pills and 10mg/day caused bad side-effects last year), I considered the use of low-dose Huperzine A (50mcg/week, say) to "top-up" the inhibition of acetylcholinesterase by Aricept.
There's always the possibility of unwanted interaction between the two substances, so I will be treading very carefully.
Nigel,
I agree with your approach.
I also need to pursue my major point about these drugs. I am not concerned about the interactions between the drugs, but rather the fact that neither drug is specific for acetylcholine esterase. The drugs affect dozens of other essential signaling and metabolic components and the side effects of each are different. I doubt that they are interchangeable and Aricept withdrawal can only be partially compensated by Huperizine A. Most of the impact on mental function probably has nothing to do with acetylcholine levels.
Your vigilance in supporting her anti-inflammatory diet probably compensated for the tendency of Aricept to cause UTIs and intestinal flareups.
I think that the UTI antibiotics will not be as hard on her gut flora as other antibiotics, but probiotic support should also be considered.
Best of luck.
I can't give mum any supplements while she's in hospital, so I have to wait until the Aricept takes effect and hope that it's effective on its own to get her into a mental state fit enough to be allowed to go home.
You were correct in predicting that statins and metformin are transported into the liver via the same organic anion transporting proteins. This transporter protein is encoded by the SLCO gene. Mutations within this protein family SLCO1B1 (domain OATP), are predicted to occur in 20% to 38% of the caucasian population, exposing a large % of the caucasian population (study of population genetics looking at this mutation was done in Finland) to greatly increased plasma levels of these drugs. Statin toxicities can run the gamut from mild myopathies (the lucky ones), peripheral neuropathies, rhabdomyolysis, and lastly most troubling and destructive(unless death results from the rhabdomyolysis), neurodegenerative diseases. Except for the association between variations in SLCO1B1, statin use and myopathies, the other adverse effects are not being studied, esp the neurodegenerative ones .
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