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Schuffenhauer et al. have used Similog keys in molecular complexity studies, [ 30 ] and other
groups have used pharmacophore-based descriptors. [ 28 ]
3.2.4 Focused Sets
Focused sets of fragment molecules may be derived for a particular class of targets, for
a specific target or from the structures of molecules with desirable biological activity.
These selections are often performed using in silico virtual screening techniques. As with
any virtual screening process, the tools that can be applied will depend critically on the
information that is available; information about the structure of the protein target and the
chemical structures of active molecules is of particular relevance.
Models of protein binding sites can be used in molecular docking studies to identify
fragment molecules with favourable binding characteristics. For example, in the identi-
fication of novel inhibitors of DNA Gyrase, Boehm et al . used molecular docking in an
in silico screening approach to identify a focused set of 3000 molecules from an initial
set of 350 000 compounds, [ 31 ] and researchers at Astex used a modified form of GOLD
docking software to select focused sets of fragment molecules from a large database of
commercially available compounds. [ 32 ]
The two-dimensional structures of known active molecules can be analysed to identify
constituent fragments, which may form the basis of substructure- and similarity-based
cheminformatics searches. During this deconstruction process, we have found it useful not
to be limited to a purely retrosynthetic approach but also to consider other approaches to
deconstructing the molecule. After all, molecular recognition does not occur on the basis of
how the ligand can be synthesised. If active conformations are known, e.g. fromX-ray crys-
tallography, these or components of them can form three-dimensional queries which could
be used in similarity searches to identify fragment molecules with low-energy conform-
ations that can adopt similar shapes. [ 33 ] In addition, three-dimensional conformations can
be used in more conventional pharmacophore searches. For instance, workers at Vernalis
used a CDK2-hymenialdisine complex crystal structure to derive a kinase pharmacophore
to select a set of focused fragment for kinase targets. [ 28 ]
Focused sets of fragment molecules have also been derived from the two-dimensional
structures of known drugs. Frequently occurring molecular features can be identified in
known drugs using computational approaches [ 34 ] and fragment molecules which exhibit
these features can then be selected from vendor collections. It has been suggested that
the chemotypes derived from known drugs may possess good properties for development
into new drugs. For example, proven chemistries should be applicable and physicochemical
properties should bemore favourable.Although these argumentsmay be true to some extent,
one has to bear in mind that it is the physiochemical properties of the whole drug molecule
that are most important, not its constituents. In addition, chemotypes that could lead to
novel drugs might be overlooked if they are not represented in the screening collection [ 35 ]
and, finally, there could be implications for the establishment of intellectual property if this
style of approach is followed exclusively.
Analysis of the hit molecules that are obtained in different fragment screening campaigns
can also yield useful information regarding active structural motifs. For example, an ana-
lysis of NMR-based screening data indicated that compounds which contain a privileged
biphenyl substructure show an enhanced probability of target binding. [ 36 ]
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