Aricept: dementia treatment

Aromatic Binding to Enzymes -- 

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.

I have presented two diagrams of the structure of Aricept. It has two isolated rings on the left and then a fused pair of rings on the right. The major chemical feature here is the inability of the rings to hydrogen bond with water. The result is that water next to the faces of the rings is highly structured in a high energy configuration. Two rings will be at a much lower energy if they are stacked together, because two of the surfaces will no longer be exposed to water.

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 to acetylcholine esterase, the enzyme that degrades the neurotransmitter acetylcholine by at least three stacked rings. These ring structures are shown in the close up of the tunnel leading to the enzymes active site near the yellow tryptophan on the left. Part of the enzyme shown by the white, ribbon-like twists of the amino acid backbone have been removed over the tope of the grey-red and blue aricept molecule, to make it easier to see.

I also showed the aricept in the tunnel with the surface of the protein shown to indicate how the aricept slips and sticks in the enzyme and blocks its activity.

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, aromatic ring amino acids. Acetylcholine, which can form hydrogen bonds with the paired electons of the acetyl oxygens, will just slip across the surface of the hydrophobic rings on its way into the enzymatic tunnel.

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 active sites of enzymes by having one of my students check for the binding of a flat hydrophobic molecule, metformin, one of the common drugs for treating type II diabetes, to a common bacterial enzyme, beta galactosidase. Kinetic studies demonstrated competitive inhibition of typical beta galactosidase substrates, which indicates that the metformin binds the aromatic amino acids that are known to be involved in binding of the sugar substrates, e.g. lactose, of the enzyme. I would not be surprised if the statins are transported into cells by the same organic cationic transporter that transports metformin.

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.