Chemistry Reference
In-Depth Information
In 2002, Dvir et al. determined the crystal structures of the complexes of HB
(47) and (
þ
)-HA with TcAChE at 2.10 and 2.35
˚
resolution, respectively.
161
The dissociation constants of (
þ
)-HA, (
)-HA, and HB were reported with the
values of 4.30, 0.18, and 0.33 mM, respectively. All three constants interact with
the ''anionic'' subsite of the active site, primarily through p-p stacking and through
Van Der Waals or C
H...p interactions with Trp84 and Phe330. Because their
R-pyridone moieties are responsible for their key interactions with the active site
via hydrogen bonding, and possibly via C
H...p interactions, all three maintain
similar positions and orientations with respect to it. The carbonyl oxygens of all
three seem to repel the carbonyl oxygen of Gly117, which thus causes the peptide
bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the
position of the main chain nitrogen of Gly118 in the ''oxyanion'' hole in the native
enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped
conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and
Ala201N, the other two functional elements of the three-pronged ''oxyanion
hole'' characteristic of ChEs. All three inhibitors thus would be expected to abolish
hydrolysis of all ester substrates, whether charged or neutral.
Wong et al. determined the crystal structures of two bis-hupyridones, (S,S)-43a
ð
n
¼
10
Þ
and (S,S)-43a
ð
n
¼
12
Þ
, the potent dual-site inhibitors of AChE.
160
The
structures revealed that one hupyridone unit bound to the ''anionic'' subsite of
the active-site, as observed for the TcAChE-(
)-HA complex, and the second
hupyridone unit was located near Trp279 in the ''peripheral'' anionic site at the
top of the gorge. Both (S,S)-43a
ð
n
¼
10
Þ
and (S,S)-43a
ð
n
¼
12
Þ
fit the active-
site gorge. The results confirm that the increased affinity of the dimeric HA analogs
for AChE is conferred by binding to the two ''anionic'' sites of the enzyme. The
structures provided a good explanation for the inhibition data showing that (S,S)-
43a
ð
n
¼
10
Þ
binds to TcAChE about 6-7- and
>
170-fold more tightly than
(S,S)-43a
ð
n
¼
12
Þ
and (
)-HA, respectively. In comparison with the crystal struc-
ture of mouse AChE, Kozikowski et al.
110
rationalized the lower binding affinity of
(S,S)-43a
ð
n
¼
10
Þ
and (S,S)-43a
ð
n
¼
12
Þ
for rat AChE, which shows that (S,S)-
43a
ð
n
¼
12
Þ
binds about three- and two-fold more tightly than (S,S)-43a
ð
n
¼
10
Þ
and (
)-HA, respectively.
4.8
ZT-1: NEW GENERATION OF HA AChE
ZT-1 is a Schiff base derivative from natural HA, and its chemical name is
[5R-(5a,9b,11E)]-5-{[(5-chloro-2-hydroxy-3-methoxyphenyl)methylene]amino}-11-
ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta[b]pyridin-2(1H)-
one. ZT-1 is a prodrug and is transformed nonenzymatically into the active
compound HA. In aqueous solution, ZT-1 is rapidly degraded into HA and
5-Cl-o-vanillin by hydrolysis. Now, ZT-1 is being developed as a drug candidate
for the treatment of AD by Debiopharm S.A. of Switzerland.
a
a
Updated information is available for ZT-1. Please visit http://www.debio.com
Search WWH ::
Custom Search