Chemistry Reference
In-Depth Information
the catabolized fragments replicate, or remain very close to, the binding geometry of the
original molecule. However, this is a simplistic view and should be used with great cau-
tion, especially in the absence of structural data. There is a report that shows that co-crystal
structures of fragments catabolized from a known -lactamase inhibitor do not bind where
expected.
[
97
]
This result suggests that there will be gaps in the molecules created through the
catabolic approach, possibly missing good lead molecules. One way to minimize this is to
use progressive catabolism. Progress catabolism is the logical way to catabolize a molecule
so that binding orientations can be tested and the portion(s) of the molecule responsible for
activity (including binding orientation) can be determined. Figure 2.4 shows an example
of progressive catabolism.
H
2
N
S
HO
O
S
OH
HO
O
O
O
A3
S
A2
O
HO
HN
CH
3
O
HO
S
O
HN
OH
O
A
OH
O
A1
Figure 2.4
Catabolism of a known inhibitor of thymidylate kinases (A) into component parts
A1, A2 and A3.
In a linking strategy, affinity is enhanced by joining two independent fragments together,
thereby realizing the gains of synergy.
[
44, 110, 111
]
This approach can use such tactics as
dynamic combinatorial chemistry and click chemistry or be the result of multiple site
fragment screening.
[
112
]
The linked hits are assumed to adopt the same geometry as the
original fragment hit(s). As with the catabolic approach, this may not always be the case.
How the fragments are linked plays a very significant role, as the wrong linker can nullify
any potential synergy gains. As shown by Alex and Flocco
[
87
]
(Table 2.1), linking is the
H2L approach most likely to result in a decrease in LE. SBDD can have a huge impact
in this approach, as it can confirm or deny the proper geometry of linked fragments.
[
111
]
This represents the 'home run' of FBDD. It can be extremely fast and efficient at producing
