G-protein coupled receptors (GPCRs) play a crucial role in many diseases and are the site of action of 25-30% of current drugs; as such they represent a major area of interest for the pharmaceutical industry. Fragment based screening using biophysical approaches is very challenging for G-protein-coupled receptors (GPCRs) due to their inherent instability outside of the cell membrane.Heptares has developed a technology that dramatically stabilizes GPCRs; the new stabilized human receptors (StaRs) are much more robust than the corresponding wild type proteins. StaR proteins can be readily purified and are amenable to crystallography, biophysical/fragment screening and for raising monoclonal antibodies.This poster will focus on the potential of the technology for structure-based drug design and fragment screening of GPCR targets. Biophysical screening results from both TINS-NMR and Surface Plasmon Resonance (SPR) binding studies and high-concentration fragment screening using an agonist StaR protein with libraries of fragments will be shown.

Fragment based approaches to GPCRs

244th National Meeting (2012)

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