GPCR Drug Discovery | Platform


Heptares has built a unique and powerful structure-based drug discovery (SBDD) capability that for the first time enables:

  • Engineering of stabilised GPCRs (StaRs®) in their natural pharmacological conformations (agonist or antagonist), including orphan receptors
  • Determination of 3D structures of GPCRs and complexes with bound ligands by X-ray crystallography and Biophysical Mapping™
  • Deployment of advanced fragment-based drug discovery approaches to GPCRs
  • Full integration of GPCR pharmacology and medicinal chemistry
  • Discovery of novel agents directed towards high-value yet historically challenging or undruggable GPCR drug targets

StaR® Technology

Heptares StaR® (stabilised receptor) technology forms the backbone of its integrated SBDD platform for targeting GPCRs. A StaR® protein is a GPCR with a small number of point mutations that greatly improve its thermostability without disrupting its pharmacology. StaR® technology is transferrable across the GPCR superfamily and allows the selection of stable, functionally relevant, purified conformations of target GPCRs that retain their expected drug-binding characteristics. Whereas unstable wild-type proteins are intractable to structural studies, StaR® proteins allow structure determination and provide the launch pad for an SBDD approach to GPCR drug targets.

StaR® -driven X-ray Crystallography

X-ray crystallography allows the precise definition of the GPCR protein structure bound to drug molecules at the atomic level. A mainstay of SBDD for other target families such as kinases, X-ray crystallography of GPCRs was previously very challenging due to the requirement for stable pure protein. Heptares approach provides a solution. StaR® proteins can be readily crystallized together with drug hits and leads, revealing previously unknown binding pockets and opportunities for small-molecule interaction with GPCR proteins. The stability of StaR® proteins permits co-crystal structures of even very weak binding compounds that are usually discovered early on in the lead generation phase of drug discovery. The detailed understanding of how compounds bind to the protein can be used by medicinal chemists to design drug candidates that fit perfectly and selectively into the ligand binding site of the receptor.

Biophysical Mapping™

In addition to X-ray crystallography, Heptares has developed a unique and proprietary surface plasmon resonance (SPR) based method for 3D determination of compound-binding modes, called Biophysical Mapping™. This novel approach enables the rapid and timely application of structural information to medicinal chemistry as soon as a StaR® protein is made, in parallel with the initial crystallographic studies. Kinetic information is also derived simultaneously. This technique can be used to screen and study fragments as well as conventional libraries and project compounds. Together with X-ray co-structures, Biophysical Mapping™ provides a powerful technology for GPCR lead discovery and optimisation.

StaR® Fragment Screening

Purified StaR® proteins allow the screening of low molecular weight fragment libraries using a variety of biophysical techniques such as SPR, NMR and capillary zone electrophoresis. Heptares has a unique fragment library optimised for GPCRs. Fragments provide an ideal starting point for drug discovery since they can fit efficiently into small pockets within drug-binding sites. Although fragments bind with low affinity they can be grown by SDBB approaches to high-affinity lead molecules that retain excellent physicochemical properties such as low molecular weight and solubility. Fragment screening has been successfully applied by Heptares to previously intractable receptors across the GPCR superfamily.

CHESS and SaBRE Technologies

CHESS and SaBRE technologies employ molecular evolution techniques to rapidly evolve panels of GPCR variants, each closely resembling the original target GPCR, and with enhanced stability and versatility for applying SBDD.

CHESS evolves functional stabilised GPCRs from populations containing hundreds of millions of variants of an ancestor GPCR, ensuring the identification of the best possible variant for downstream drug discovery applications. When applied to an attractive GPCR, CHESS delivers correctly folded GPCRs that can be purified and stored in a ligand-unbound state. These GPCRs can be expressed using inexpensive hosts, such as E. coli, to produce high quality protein in order to accelerate drug discovery.  CHESS delivers GPCR targets that are stable enough to conduct high-throughput drug screening and selection of biologics, as well as various structural and biophysical techniques.

SaBRE (Saccharomyces cerevisiae-based receptor evolution) expands the directed evolution technology to a eukaryotic host, which allows the generation of improved receptor variants of even the most difficult-to-express members of the GPCR superfamily.

Structure of StaR® protein in complex with an antagonist compound (grey) discovered by Heptares using its SBDD approach. StaR® protein represented in chainbow cartoon representation (N terminus blue, C terminus red).


Fragment bound to GPCR at 3.25A resolution.

© 2012-2017 Heptares Therapeutics