Chemistry Reference
In-Depth Information
Flap region
S
2
pocket
S
1
pocket
O
3
H
N
1
H
O
N
N
H
H
O
S
3
pocket
Asp
228
O
O
Asp
32
Figure 11.9
Binding model for
5
bound to BACE. This model was generated from a low-
resolution crystal structure and computational analysis.
O
HN
5
IC
50
570
H
2
N
N
m
M
LE 0.28
O
O
H
3
C
HN
N
H
H
2
N
H
2
N
N
N
10
IC
50
86
9
IC
50
183
m
M
LE 0.29c
m
M
LE 0.30
O
H
3
C
N
11
IC
50
16
H
H
2
N
N
m
M
LE 0.33
N
Figure 11.10
Starting from
5
,
N3
methylation and indole incorporation led to the identifica-
tion of
11
.
series with affinity less than 10 M. Ahigh-resolution crystal structure was obtained for the
14
-BACE complex
[
42
]
(Figure 11.11) and it precisely confirmed the binding model shown
in Figure 11.9. In addition to the hydrogen bonding contacts with the catalytic aspartates
(Asp32 andAsp228), there is a hydrogen bonding contact between the isocytosine carbonyl
and the main-chain amide NH from Gln73. Residues 72 and 73 comprise the flap region,
which closes down over the ligand in this case. The bis-aryl region fills the S
1
/S
3
pocket
and opens a deep pocket at the bottom of S
3
to accommodate the methoxy substituent.