Platform Technology

Application of structure-based drug discovery to G Protein-Coupled Receptors

By Rob Cooke | May 2, 2019


30th Symposium on Medicinal Chemistry in Eastern England
2 May 2019
Hatfield, Hertfordshire, United Kingdom
Royal Society of Chemistry | Biological & Medicinal Chemistry Sector

Conference Website


G protein-coupled receptors (GPCRs) are an important and long-standing family of drug targets. Despite many historical success stories, today there are still a significant number of GPCRs with compelling pre-clinical validation that remain highly challenging for drug discovery. Over the last 10 years there has been great progress in the structural biology of GPCRs facilitating Structure-Based Drug Design (SBDD) approaches. Sosei Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a chosen conformational state. These purified proteins can then be used for biophysical screening techniques and crystallisation to yield X-ray structures with multiple ligands.

Using the StaR® approach, Sosei Heptares has solved structures of many GPCRs, revealing the details of both orthosteric and allosteric binding sites. In some GPCRs, notably Class B members that bind large peptides, the orthosteric binding sites are open, mostly occupied by bulk-like solvent, and are extremely challenging from a SBDD perspective. In contrast, allosteric ligands usually bind in smaller sites with both hydrophobic and hydrophilic regions, making them more tractable for small molecule drug discovery.

An overview of how the StaR® platform has enabled SBDD approaches for GPCRs will be given. Structure-driven medicinal chemistry campaigns for several important GPCR targets will be outlined as a series of short case studies, illustrating how SBDD can give differentiated chemical series compared with empirical approaches.

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