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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.
 
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