A new paper in Molecular Pharmacology describes how 'reverse pharmacology', enabled by Heptares Therapeutics StaR(R) technology, can be applied to and accelerate GPCR-based drug discovery.

The paper utilized the study of isolated GPCRs locked in conformations that correspond to agonist or antagonist pharmacology, and the elucidation of their respective 3D structures. These StaRs and structures can be used to select and design compounds with specific pharmacologies, such as inverse agonist, partial agonist or full agonist, based on their ability to bind differentially to the agonist and antagonist StaRs. For example a full agonist will preferentially bind to the agonist StaR. 

This approach is termed 'reverse pharmacology' since classically compounds are made and tested in cells and tissues, and only then can their preferred receptor conformation and activity be determined, a process subject to variation depending on the assay system and lacking precision.

"The ability to predict whether a compound will behave as an agonist, inverse agonist or antagonist in an in vitro, in silico or in vivo setting is a very powerful tool for drug discovery," said Fiona Marshall, Heptares' Chief Scientific Officer. "Combining this approach with our unique StaR technology is enabling Heptares to advance our pipeline of novel compounds targeting important GPCR targets, and those of our partners, towards the clinic."


Bennett, K.A. et al. Pharmacology and Structure of Isolated Adenosine A2A Receptor Define Ligand Efficacy, 2013, Mol. Pharmacol. doi:10.1124/mol.112.084509