Discussion

Fragment-based drug discovery is critically dependent on the availability of X-ray structures of
protein-fragment complexes to efficiently develop them into lead compounds. Traditionally,
screening libraries directly by crystallography has been a daunting challenge. However, modern
synchrotron facilities like Diamond Light Source have ushered in a step-change in the speed of the
diffraction experiment, and through deployment of high-throughput robotics, coupled with
automated data processing, now allow many 100s of datasets to be collected per day. The
bottleneck has thus decisively shifted upstream to sample preparation.
Diamond now offers fragment screening into crystals as a routine facility experiment at beamline
I04-1, supporting the full process from soaking to dataset. The sample preparation bottleneck has
been effectively addressed by new protocols for efficient compound handling and sample
preparation, combining texture-based image recognition, acoustic liquid handling, and robot assisted
crystal harvesting into a pipeline that enables soaking and harvesting the full complement
of crystals of a screening experiment in a single day.
Evotec is the first commercial group to access the facility and is collaborating with Diamond to
evolve the pipeline to suit the needs of existing and future industrial users. Drawing on Evotec’s
significant experience in fragment-based approaches, the collaboration is investigating
streamlining the system for industrially relevant projects and bespoke fragment libraries. Here we
outline the general workflow, describe novel technologies and present results from recent trials
performed by Evotec.