Acetylcholinesterase drug targets

Once synthesized, acetylcholine is stored in synaptic vesicles until time for its use. Once liberated into the synapse, acetylcholine diffuses across the synaptic cleft in about 100 microseconds (10 " seconds one ten-thousandth of a second), where it interacts with its receptor, and then dissociates from it in the next 1 or 2 milliseconds. Once liberated, acetylcholine is degraded by a second enzyme, acetylcholinesterase, a target for drug discovery (as I develop a bit later). 

Lorke/ D.E., Hasan, M.Y., Nurulain, S.M., et al., 2012. Acetylcholinesterase inhibitors as pretreatment before acute exposure to organophosphates assessment using methyl-paraoxon. CNS Neurol. Disord. Drug Target 11,1052-1060. 

H. M. Greenblatt, H. Dvir, 1. Sdman, J. L. Sussman Acetylcholinesterase a multifaceted target for structure-based drug design of anticholinesterase agents for the treatment of Alzheimer s disease. J Mol Neurosci 2003, 20, 369-383. 

Acetylcholinesterase is a remarkably efficient enzyme turnover has been estimated as over 10 000 molecules per second at a single active site. This also makes it a key target for drug action, and acetylcholinesterase inhibitors are of considerable importance. Some natural and synthetic toxins also function by inhibiting this enzyme (see Box 7.26). 

Acetylcholinesterase is the primary target of these drugs, but butyrylcholinesterase is also inhibited. Acetylcholinesterase is an extremely active enzyme. In the initial catalytic step, acetylcholine binds to the enzyme s active site and is hydrolyzed, yielding free choline and the acetylated enzyme. In the second step, the covalent acetyl-enzyme bond is split, with the addition of water (hydration). The entire process occurs in approximately 150 microseconds. 

In addition to the examples discussed above, the structures of many clinically and biologically important proteins have been determined. Some of these are amenable to immediate use in drug discovery efforts. These include enzymes such as dihydrofolate reductase (Jansy, 1988), and thymidilate synthase (Appelt et al, 1991) both of which are involved in the synthesis of DNA precursors. Their inhibition is a target in anticancer chemotherapies. Structures of other proteins such as cAMP-dependent protein kinase, acetylcholinesterase, and the glucocorticoid receptor add to the knowledge base that will open new avenues... 

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