Navigating the Orthosteric and Allosteric Structural GPCR Pocketome for Structure-Based Drug Discovery
Sonja Peter1,2, Anna Palló1, Ijen Chen1 and Chris de Graaf1
1Sosei Heptares, Cambridge, UK
2University of Urbino “Carlo Bo”, Urbino, Italy
G protein-coupled receptors (GPCRs), the largest family of cell signalling trans-membrane proteins, are regulated by diverse small molecules. Allosteric modulators interact with binding sites topologically distinct from the orthosteric ligand binding sites, which can be the extracellular, intracellular, or extrahelical allosteric sites . However, the identification of allosteric binding sites has been challenging due to the high diversity of binding modes and protein plasticity upon ligand binding. Recent advances in GPCR structural biology  have allowed a more in-depth examination of allosteric modulators.
Here we describe the development and the application of structural bioinformatics and chemogenomics methods to assess ligands from the structural GPCRome . This includes druggability assessment for the ligand-binding sites and chemoinformatics analysis on the bound ligands. Results are discussed to get a better understanding of all the flavors of allosteric ligands in relation to the orthosteric binders. This work aims to provide an overview and characterize the current GPCR allosteric binding site structure landscape with exciting potential for GPCR drug discovery.
This project receives funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 956314.
 Chris de Graaf et al. “Extending the structural view of class B GPCRs”. In: Trends in biochemical sciences 42.12 (2017), pp. 946–960.
 Miles Congreve et al. “Impact of GPCR structures on drug discovery”. In: Cell 181.1 (2020), pp. 81–91.
 Márton Vass et al. “Chemical diversity in the G protein-coupled receptor superfamily”. In: Trends in Pharmacological Sciences 39.5 (2018), pp. 494-512