Chemistry Reference
In-Depth Information
N
+
N
+
H
H
N
Asp32
Asp32
N
H
H
H
H
Asp228
Asp228
Figure 9.8
Two aminopyridine fragments depicted in their binding modes with BACE-1
active site.
where IC
50
could also be p
K
i
or p
K
d
and the assay results are normalized by molecular
weight (MW). LE is calculated by normalizing the free energy by heavy atom count (HAC)
via the following equation:
LE
=−
G/
HAC
≈−
RT
ln
(
IC
50
)/
HAC
(9.2)
The calculated LEs for the fragments in Figure 9.8 are 0.33. The Astex fragments are
assumed to have an IC
50
of
∼
2mM and with molecular weights of
∼
145 Da their calculated
BEI values are
18. When compared with other targets, the LE and BEI values for the
BACE-1 target are lower, which implies that values such as BEI and LE need to be applied
in a target-specific context.
[
3
]
The other approach taken by Murray
et al
. is that of virtual screening. Virtual screening
is not new to the BACE field and has been applied many times to reveal new compounds
of interest.
[
23
]
In addition to the fragment library already described at Astex, the Astex
Therapeutics Library of Available Substances (ATLAS) and their corporate collection of
compounds was virtually screened. They applied the following property restrictions in vir-
tual screening of these two collections of compounds: molecular weights <300, CLogP <3
and the number of HBDs <4. In addition, the list of chemical suppliers was restricted to
those with which they had prior experience. Their 3D virtual screen, which consisted of
docking the compounds which satisfied the aforementioned criteria into the BACE-1 active
site, was guided using pharmacophoric constraints. That is, they specifically searched for
compounds which contained the key chemical features identified in the compounds depicted
in Figure 9.8. Hydrogen bonding interactions with Asp228 and Asp32 were preferentially
selected in the virtual screening studies. It is known that BACE-1 is an inherently flexible
enzyme and can exist in many protein conformations. Therefore, in their virtual screening
protocol, the compounds were docked using a proprietary version of GOLD
[
26, 27
]
and scored
and ranked using both GoldScore
[
28
]
and ChemScore
[
29
]
in multiple protein poses. Using
the results from virtual screening as a guide to select 65 compounds for crystallographic
studies, they found that eight compounds (12%) soaked into the BACE-1 active site. One
of these compounds, depicted in Figure 9.9, has an IC
50
of 310 M with corresponding
LE (BEI) value of 0.32 (17.5). Two additional fragments were identified which make con-
tacts with the catalytic aspartic acids: a piperidine and a hydroxyethylmorpholine. Murray
∼
