Chemistry Reference
In-Depth Information
of constituents possible through reversible chemical reactions between component frag-
ments. The composition of aDCLis governed by the thermodynamic stability of the possible
constituents under the conditions of the experiment, meaning that a change in the library
environment can instruct and inform changes in the library composition. Libraries are there-
fore not static (as in conventional combinatorial chemistry) but can alter in composition
through the re-equilibration of their reversibly linked fragments, for example in response
to the presence of a selection pressure in the immediate environment such as the addition
of a target biomolecule. The shift in equilibrium that occurs with this adaptive chemistry
leads to an increase in the concentration of the library molecule(s) that best recognizes
(through molecular recognition) the target (Figure 7.2). The dynamic chemistry may occur
both untemplated, in the bulk solution, or templated, within the target's active site. Either
way, the target-selected linked fragments are withdrawn from the solution equilibrium and
the DCL then re-equilibrates to produce more of these selected products at the expense of
other possible products. Hence the most active DCL constituents are selected and ampli-
fied in the presence of the target. The diversity of a DCL is on two distinct levels: the first
is fixed and dependent solely upon the number and molecular architecture of the initial
fragments, whereas the second is the diversity accessible upon linking these fragments to
generate the library constituents and hence can alter under different library conditions (i.e.
in the presence of different targets). The composition and diversity of DCLs are
informed
and are driven by the target rather than governed by sheer numbers alone. Provided that
a molecule is accessible with the reversible chemistry and available fragments, it may be
selected and amplified in the presence of a target, circumventing the need for the synthesis
and even representation of every library member. One appealing advantage of DCC is that it
readily lends itself to the optimization of fragments identified as privileged for a particular
therapeutic target.
high affinity
ligand
target
biomolecule
Y
X
Y
X
Y
X
DCL
Fragments with
complementary functional
groups (X and Y) for DCC
Figure 7.2
Schematic representation of
target-templated
in situ
dynamic combinatorial
chemistry.
7.4 Dynamic Combinatorial Chemistry - Reversible Chemistry
The key feature of DCC is the reversible chemical reaction that mediates exchange
of the building block fragments.
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For
in situ
drug discovery applications of DCC,
the selection of linked fragments occurs in the same environment as the equilibration
reaction and this demands that the reaction fulfils several requirements in addition to
