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most potent and selective human AChEIs among them. They showed high inhibi-
tory
activity
toward
human
AChE
(hAChE)
with
IC
50
values
of
0.318
and
0.323 nM, respectively.
Additional studies on 49a and 49b have shown that both compounds act as the
tight-binding and reversible AChEIs. They cross the blood-brain barrier and bind to
the hAChE with a K
i
value of around 30 mM, which is one of the highest affinities
reported in the literature. The affinity of both compounds for hAChE is 180-fold
higher than that of HA.
142,143
4.7
STRUCTURAL BIOLOGY
4.7.1
Interaction Between HA and AChE
The crystal structure of the complex of Torpedo californica AChE (TcAChE) with
natural HA at 2.5
˚
resolution was conducted by Raves et al.
144
The result showed
an unexpected orientation for the inhibitor, with surprisingly few strong direct inter-
actions with protein residues to explain its high affinity. HA was found to be bound
with aromatic residues in the active site gorge of TcAChE, which localizes between
tryptophan at position 86 (Trp86) and tyrosine at position 337 (Tyr337) in the
enzyme.
9
Only one strong hydrogen bond is formed between the pyridine oxygen
of HA and Tyr130. The ring nitrogen hydrogen binds to the protein through a water
molecule. The hydrogen-bonding network is formed between the -NH
3
group and
the protein through several waters (Figure 4-6a). The perfected orientation of HA
within the active site makes the ethylidene methyl group form a cation-like (or
termed the C
H
p hydrogen bond) interaction with Phe330 (Figure 4-6b). The
H440
H440
E199
G117
Y121
2.98
2.98
Y70
2.57
F330
F330
2.81
4.34
2.65
2.65
3.02
2.41
3.85
3.07
2.59
2.60
3.46
2.90
Y130
3.15
2.64
W84
W84
D72
N85
A
B
Figure 4-6. The interactions of (
)-HA with the active site of TcAChE. (a) The hydrogen
bonding networks. The water molecules are represented by red balls. (b) The C
H...p
hydrogen bonds. The distances are given in ˚ngstr ¨ms. Copy from Ref. 10.
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