Chemistry Reference
In-Depth Information
3.2.5
Synthetic Aspects
The low potency of the hits obtained from the fragment or reduced complexity screening
(RCS), compared with those of HTS hits, makes significant optimisation of the ligand
potency necessary. Several different synthetic strategies can be applied to achieve this,
typically by fragment evolution or fragment linking. Target-guided fragment self-assembly
(dynamic combinatorial chemistry) has also been reported.
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Whatever strategy is chosen,
it is highly desirable for the fragment hits to have at least one, or preferably a few, synthetic
handles (functional groups) for rapid structural expansion/modification.
The most simple and effective but labour-intensive way of including this synthetic
expandability criterion in the fragment library design process is visual inspection of the
fragments by medicinal chemists. Scientists at Vernalis visually inspected their fragment
set to identify potentially insoluble fragments and to ensure that most fragments con-
tained suitable functional groups to allow rapid chemical evolution of each fragment
scaffold.
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Astex also employed a similar approach for ensuring the presence of selec-
ted functional groups to make their fragments chemically tractable and suitable for rapid
optimization.
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In order to ensure that every fragment represents a good synthetic starting point, it
would be ideal to use building blocks such as those used for combinatorial and parallel
synthesis. Many chemical suppliers offer a wide range of compounds for this purpose.
However, it would be advantageous if such selections of building blocks could be enriched
with substructures of biologically active molecules or privileged motifs found in known
drugs. Using the Retrosynthetic Combinatorial Analysis Procedure (RECAP), Lewell
et al
.
performed fragmentation of the compounds in the Derwent World Drug Index (WDI) at
11 predefined bond types in a retrosynthetic fashion. These bond types were carefully
chosen so that all the resulting fragments were amenable to combinatorial chemistry using
standard synthetic procedures.
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An alternative approach, similar to RECAP, referred to
as SHAPES, has been described by the group at Vertex. The original SHAPES library has
been further expanded to the SHAPES linking library. Synthetic accessibility aspects have
been taken into account in the design of the new library so that the linkers and side-chains
contained in the compounds in the library are compatible with the reactions implemented
by the Vertex combinatorial chemistry group.
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The drawback of selecting building blocks as screening fragments is their reactivity.
Very reactive compounds such as acid chlorides, isocyanates and alkyl halides are not
suitable for fragment screening. Even functional groups of low reactivity that are often
used as synthetic handles in building blocks, such as carboxylic acids and amines, can
cause problems. Analysis of the literature carried out by scientists at Novartis revealed
that hits containing these groups, especially carboxylic acids, often lose binding when
these groups are used as a synthetic starting point during fragment evolution.
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Functional
groups such as the amino group or the carboxylic group, not only offer potential for chemical
modification, but also can be a keymotif for fragment-protein interaction due to their ability
to form strong hydrogen bonds and ionic interactions.
Functional group masking is a strategy to circumvent this problem, in which fragments
containing chemically inert products of reactive functional groups (masked functional
groups) are used for screening. Once hit compounds have been identified, the unmasked
chemical handle is used for further chemical elaboration. Ellman and co-workers
