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Acetylcholinesterase (AChE) is the most important enzyme in vertebrate nervous system. It hydrolyses the neurotransmitter
acetylcholine (ACh) into choline and acetate. It is involved in transmission of signals between nerves and between nerves
and muscles. In recent years, there is increasing evidence to support the involvement of ACh and AChE in non-neuronal
function in animals as well as in plants. Chemicals that inhibit AChE or a related enzyme butyrylcholinesterase (BChE) are
known as anticholinesterases (AntiChE). AntiChE like organophosphates (OPs), which are commonly used in chemical
warfare (nerve agents), can inactivate AChE. The resulting accumulation of acetylcholine (ACh) in cholinergic synapses can
lead to the failure of cholinergic synaptic transmission, deterioration of muscular junctions, flaccid muscle paralysis, seizures
in the central nervous system and can lead to death. A potential long term strategy for preventing AChE inactivation by
OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge
before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is
to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally
with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict
access, much more information must be gathered about the structure−activity relationships of ligands that bind specifically
to the P-site. An inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the
A-site, or both sites is used. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including
aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to
bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently
been confirmed by X-ray crystallography (Cheung, J. et al., 2013). Dihydrotanshinone I, with an observed binding constant
(KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for
the P-site.
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