15
chemistry. "Bad actors" such as reactive covalent modifiers, chelators, and other types of aggregators need to be
excluded or purged from the library to reduce false positives. This work is much easier and cheaper at the 1000-fold
lower scale of fragment libraries.
The higher hit rates that fragment screening offers, has the very important benefit of significantly
expanding the classes of targets into more difficult areas, such as protein-protein interactions.
Another useful characteristic of fragments that appeals to big pharma and small biotech
alike is the greater solubility of the smaller compounds at the high concentrations
needed to carry out the screens.
The success of FBDD has already had
a large impact on other drug discovery
strategies. Principles of FBDD such
as tight quality control of compound
libraries, biophysical validation of
protein-ligand interactions, and hit
optimization driven by SAR have gained
widespread use in drug discovery and
are being applied to HTS campaigns.
Big pharma companies are cleaning up
their compound archives and validating
hits identified using biochemical assays
with biophysical methods.
The future
of FBDD
5
Successful use of NMR and X-ray
crystallography in acquiring structural
information on fragment leads
bound to protein targets, has led to
these techniques becoming primary
screening tools for FBDD at many
companies. However, their entrenched
use in screening can present limitations
on the types of commercially
interesting targets a company might
wish to pursue, because structural data
using these methods may not be easily
obtained in some target classes. While
