Chemistry Reference
In-Depth Information
4
Practical Aspects of Using NMR in
Fragment-based Screening
Johan Schultz
4.1
Introduction
Fragment-based screening (FBS) has attracted much attention in the pharmaceutical
industry since its emergence 10 years ago and is now widely used as an alternative or
complementary approach to traditional screening. [ 1 6 ] The basic idea is to
screen only a small number of small molecules ('fragments'), typically somewhere
between 100 and a few thousand fragments;
find weakly binding but efficient (high binding energy per atom) binders;
develop the binding fragments into more potent compounds using fragment expansion,
merging or linking while maintaining a high ligand efficiency.
Only a relatively small number of fragments need to be screened since the hit rate
will be much higher than with traditional screening. This is a consequence of lower com-
plexity fragments having a higher probability of matching a target protein binding site. [ 7 ]
Further, since the number of theoretically possible molecules increases exponentially with
the number of atoms in the molecules, screening a small fragment library, typically 10 2 -10 4
compounds, samples substantially more chemical diversity space than a conventional HTS,
where typically 10 5 -10 6 larger compounds are screened. [ 8 ] The detected fragment binders
will, however, bind to the target macromolecule with a relatively low affinity since they
contain relatively few features that can interact with the target. Fortunately, there are sev-
eral biophysical techniques that are well suited to detect weak binding events reliably.
 
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