The Structural Biology group is central to the operation of the DDP. Responsible for Fragment-Based hit identification, this group provides expertise across protein production, NMR, SPR and X-ray crystallography. A state-of-the-art 600Mhz NMR with cryo-cooling and sample changer is used as the primary screening technology for Fragment-Based hit identification. In addition, as support for day-to-day chemistry/small molecule NMR, a 400MHz instrument with sample changer is employed.
Fundamental to Fragment-Based hit identification is the provision of orthogonal techniques to confirm the validity and suitability of hits for further work. While one aspect of this is (high concentration) biochemical screening, an orthogonal biophysical technique is also required. In our case, we use Surface Plasmon Resonance (SPR). SPR provides valuable information on both the stoichiometry as well as the kinetics of binding. These are fundamental characteristics that can critically inform for both validation as well as prioritisation of hits.
The X-ray crystallography group generates high resolution structural information to understand protein-ligand interactions in screen hits, Hits-to-Leads and Lead Optimisation compounds in order to drive design. The work is integrated with computational and medicinal chemistry to maximise the impact of the structural data generated and exploit a range of structure-based design methods. For programmes that are amenable to crystallographic studies, the Structural Biology group has the opportunity to work with the research groups and facilities of Danny Huang and Shehab Ismail to further enhance structural support.