Chemistry Reference
In-Depth Information
C
a
-C
a
(Q73) 7.1Å
Figure 9.13
Highlighting the large 10s loop movement in the BACE-1 active site using crystal
structures 1W50 and 1W51.
10
9
8
7
6
5
4
3
-70
-65
-60
-55
-50
Interaction Energy (kcal/mol)
Computed using MMFFs
r
2
= 0.89
Figure 9.14
Correlation between binding energy calculated using MMFFs
[36]
and measured
Ki for a diverse set of ligands in P3 pocket.
These results were used to screen a virtual database of primary amine fragments to enhance
binding affinity in the P3 pocket using a related scaffold as shown in Figure 9.15. The virtual
screening was quickly accomplished through Merck's in-house web-based tools described
in Section 9.6 and was in fact a test of these tools.
In the present BACE-1 example, over 9000 amine fragments were combined with the
scaffold in Figure 9.15. Up to 25 conformations for each fragment were sampled with the
resulting
25 000 molecules individually energy minimized and scored in two conform-
ations of the BACE-1 active site, one with the 10s loop up and the other with the 10s
loop down. In this retrospective analysis, MFCD00041323, the known active component,
ranked 51 out of the >9000 candidates with a
K
i
of 42.4 nM.
[
40
]
In this case the best fit was
with the 10s loop up, which is consistent with the crystal structure shown in Figure 9.16,
pdb code 2IRZ.
∼
