Chemistry Reference
In-Depth Information
Virtual fragment screening has also been performed at Merck for BACE-1. Two examples
of fragment-based screening are described below. The first involves the virtual screening
of
700 amines in the P1
pocket, resulting in the identification of new BACE-1 inhibitors.
The second example is a retrospective analysis of the virtual screening of the P3 pocket with
>9000 amines. In this case, the objective is to identify a fragment with known activity out
of the background of the
∼
∼
9000 other primary amines as a test of the Merck's proprietary
web tools described below.
In the first example of virtual screening of fragments to enhance binding affinity, a set of
P1
substituents were selected prospectively for the BACE-1 inhibitor scaffold depicted at
the top of Figure 9.10. Note the scaffold includes an -methylbenzylamide P3 substituent
which is the target of the retrospective analysis in the second example. While the loop
conformation near the P3 pocket is shown below to be important for scoring P3 substituents,
all fragments in the present example were scored in a single conformation of the BACE-1
active site, consistent with the crystal structure of this compound series. The 'real' and
'virtual' chemistries employed in this reagent scan are also shown in Figure 9.10.
O
S
O
N
F
OH
H
H
H
N
Real Chemistry
N
R
O
O
2HCl
OH
OH
O
BocHN
BocHN
NHR
H
2
N
NHR
NH
2
R
Isopropanol
85°C
HCl (g)
EtOAc: MeOH (3:1)
Virtual Chemistry
Figure 9.10
P1
amine substituents were selected prospectively for a BACE-1 inhibitor scaf-
fold. Note the dashed circle (above) and dashed line (below) indicating the point of attachment.
The real (top) and virtual (bottom) chemistries are depicted beneath the scaffold.
A set of 701 suitable amine reagents was selected from the ACD.
[
35
]
After generation
of up to 25 conformers per fragment, a total of 13 089 conformers of 701 virtual BACE-1
