Structural Chemogenomics in G Protein-Coupled Receptor Drug Discovery
Conor C. G. Scully1, Robert T. Smith1, Benjamin G. Tehan1, Francesca Deflorian1, Juan Carlos Mobarec1, Andreas Bender2, Jonathan S. Mason1, Chris De Graaf1
2University of Cambridge
G Protein-Coupled Receptors (GPCRs) are a family of approximately 400 cell membrane bound receptors binding a range of chemotypes including small molecules, peptides, lipids and proteins. Targeting GPCRs in drug discovery has been extremely fruitful, approximately 30% of currently approved drugs exert clinical effects through GPCRs.
Despite past success, new avenues in GPCR drug discovery continue to be opened up by recent advances in technology and research. New 3D structural characterization of receptors though X-ray crystallography and cryo-electron microscopy has reinvigorated structure-based drug design (SBDD) as applied to GPCRs. Novel crystal structures of GPCR-ligand complexes solved at Sosei Heptares and elsewhere continue to reveal a diversity of potential ligand binding sites, such as new allosteric binding sites for Class A and Class B GPCRs. Structural elucidation of receptors has been accompanied by wide ranging site-directed mutagenesis (SDM) studies and the aggregation and annotation of vast amounts of GPCR bioactivity and binding data into both public and commercial molecular databases.
The availability of such a wealth of structural and chemoinformatic information allows the construction of a computational framework for a structural chemogenomics-driven approach to GPCR drug discovery. Integrated workflows will be described that combine structural, pharmacological, and chemical data to explore receptor-ligand interaction space  and steer structure-based virtual ligand screening approaches. In addition, a detailed survey of GPCR medicinal chemistry space has been carried out using the CHEMbl and Reaxys Medicinal Chemistry databases. Building on the ability of ligands for one receptor to modulate other GPCRs, curation of receptor ligand sets followed by clustering and cross-family similarity searches resulted in the identification of novel small molecule and peptide-based ligands for receptors from across the GPCR superfamily. Examples and applications of small molecule and peptide structure-based SAR analysis and design in the GPCR field will be presented in the context of this work.
The data generated through this system drives innovative approaches to hit discovery, lead optimization, off-target predictions and drug repurposing. We will demonstrate how ligand-based approaches (e.g. GPCR cross-family molecular similarity and ligand 3D shape-based analysis) and target-based approaches (e.g. protein structural alignments, protein-ligand 3D interaction fingerprint comparison, as well as analyses of receptor sequences, water networks, lipophilic hotspots and binding site similarity) complement each other to form an information-rich environment for drug discovery[3, 4]. Congreve, M., Oswald, C., and Marshall, F.H. (2017). Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Trends in Pharmacological Sciences 38, 837–847.  Vass, M., Kooistra, A.J., Yang, D., Stevens, R.C., Wang, M.-W., and de Graaf, C. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends in Pharmacological Sciences 39, 494–512.  Mason, J.S., Bortolato, A., Weiss, D.R., Deflorian, F., Tehan, B., and Marshall, F.H. (2013). High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacology 1, 23.  Bortolato, A., Tehan, B.G., Smith, R.T., Mason, J.S. (2018) Methodologies for the Examination of Water in GPCRs. Methods in Molecular Biology, 1705, 207.