Guest post from Heptares on Structure Based Drug Design

Friday, 6 February 2015

Structure based drug design (SBDD) involves obtaining the X-ray structure of a protein and using information about the shape and charge of the binding pocket to design drugs which can efficiently block or activate the protein of interest. This approach has been very successfully applied to enzyme targets and has resulted in drugs for the treatment of diseases such as HIV, hepatitis and cancer. The last few years has seen numerous advances in our ability to solve the X-ray structures of membrane proteins including GPCRs (G protein-coupled receptors), a superfamily of receptors linked to a wide range of human diseases. These have come from improvements in expression, purification, new detergents, protein engineering and X-ray analysis. Of particular note is the understanding that protein instability has been a key stumbling block in solving GPCR structures and this has been addressed by the StaR® technology used by Heptares Therapeutics and pioneered by Chris Tate and Richard Henderson at the Laboratory of Molecular Biology in Cambridge. The StaR method involves introducing a small number of carefully selected mutations into the GPCR sequence that increases the thermostability and conformational flexibility.


Heptares has recently joined forces with AstraZeneca to utilise its experience in SBDD for an important target of interest to AstraZeneca. The protease activated receptor PAR2 is an unusual GPCR which is activated by cleavage with a protease enzyme. The receptor is expressed on primary afferent neurones involved in pain sensation. PAR2 appears to play a key role in neurogenic inflammation and pain in particular associated with cancer and gastrointestinal pain. Because of the unusual mechanism of activation, which leaves part of the receptor to act as its own ligand, it has proved extremely difficult to identify small molecule antagonists which could be used as a treatment for such pain conditions. In the collaboration with AstraZeneca, Heptares scientists generated a StaR version of PAR2 and used this for screening compound libraries as well as solving the world’s first X-ray structure of PAR2. For the first time we are able to see in detail the unusual binding pockets of the PAR2 receptor and identify small molecule compounds which could fit into these pockets and block activation of the receptor. This information is now being used by teams of computational and medicinal chemists at AstraZeneca to further optimise the molecules – increasing their binding affinity, potency as antagonists as well as improving properties that are needed in drug molecules such as oral bioavailability and metabolic stability. Comparison of the PAR2 structure with that of related GPCRs allows us to understand how to build selectivity into the compounds. This is important as the most closely related receptor – PAR1 is present on platelets and is involved in blood clotting. Avoiding activity at PAR1 which could lead to undesirable side effects is an important consideration during the lead optimisation process.


The collaborative approach taken by AstraZeneca and Heptares has been successful in solving the X-ray structure of PAR2 and using this to identify small molecule antagonists at the receptor. Further optimisation of these compounds is ongoing and this will allow the scientists to evaluate for the first time the full potential of PAR2 antagonists in different types of pain. There is a huge need for new drugs to treat pain and blockade of the PAR2 receptor is one of the most exciting new approaches currently being evaluated.

Watch the video to learn more about the collaboration with Heptares