Chemistry Reference
In-Depth Information
added a new dimension to the synthetic capability of medicinal chemistry as the target
assists the medicinal chemist to select and synthesize those reaction products that have a
high affinity for the target from all potential reaction products that are accessible through
the chemistry employed. Target-guided synthesis is readily conceptualized by the familiar
'lock and key' host-guest descriptors of Emil Fischer (Figure 7.1), wherein the biomolecu-
lar target acts as the host to facilitate the 'correct'assembly of fragment components leading
to the synthesis of a guest small molecule. This description equally encapsulates the prin-
ciple of
in situ
chemical linking of fragments for application to drug discovery. The latter
can be subdivided into two complementary approaches:
in situ
DCC (linking fragments
under thermodynamic control) and
in situ
Click chemistry (linking fragments under kinetic
control).
target
biomolecule
Target-guided
synthesis
fragment building blocks
Figure 7.1
Schematic representation of target-guided synthesis to generate a ligand (guest)
templated by a target biomolecule (host) using the 'lock and key' descriptors of Emil Fischer.
7.3 Dynamic Combinatorial Chemistry - an Overview
Conventional combinatorial chemistry permits the rapid synthesis of small-molecule lib-
raries and the impact of this development has been to revolutionize synthetic chemistry.
When applied in a drug discovery setting, the sheer number of compounds generated,
when coupled with high-throughput screening, in principle could facilitate a speedier
route to drug lead discovery compared with the traditional single compound/single assay
strategy. Vast numbers of compounds have not had the level of impact that one might have
expected, however, mostly owing to inappropriate compound selection, and this realization
has encouraged drug lead discovery programmes to challenge synthetic efforts to capture
biological relevance better.
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Dynamic combinatorial chemistry (DCC) offers a conceptually different approach to the
synthesis and screening of libraries of small molecules for drug discovery compared with
conventional combinatorial chemistry.
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These libraries are called dynamic combinator-
ial libraries (DCLs) and are generated from the reversible reactions between a set of building
blocks or fragments to give a library of covalently, but reversibly, linked fragments. In a
DCL all linked fragments, i.e. constituents, are thus in equilibrium, with interconversion
