Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential

J Chem Inf Model. 2024 Nov 11;64(21):8176-8192. doi: 10.1021/acs.jcim.4c00819. Epub 2024 Oct 23.

Abstract

The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations of allosteric modulation, and yet few drugs target them. This gap highlights the need for a deeper understanding of allosteric modulation in GPCR drug discovery. The current work introduces a systematic annotation scheme to structurally classify GPCR binding sites based on receptor class, transmembrane helix contacts, and, for membrane-facing sites, membrane sublocation. This GPCR specific annotation scheme was applied to 107 GPCR structures bound by small molecules contributing to 24 distinct allosteric binding sites for comparative evaluation of three binding site detection methods (BioGPS, SiteMap, and FTMap). BioGPS identified the most in 22 of 24 sites. In addition, our property analysis showed that extrahelical allosteric ligands and binding sites represent a distinct chemical space characterized by shallow pockets with low volume, and the corresponding allosteric ligands showed an enrichment of halogens. Furthermore, we demonstrated that combining receptor and ligand similarity can be a viable method for ligandability assessment. One challenge regarding site prediction is the ligand shaping effect on the observed binding site, especially for extrahelical sites where the ligand-induced effect was most pronounced. To our knowledge, this is the first study presenting a binding site annotation scheme standardized for GPCRs, and it allows a comparison of allosteric binding sites across different receptors in an objective way. The insight from this study provides a framework for future GPCR binding site studies and highlights the potential of targeting allosteric sites for drug development.

Publication types

  • Comparative Study

MeSH terms

  • Allosteric Regulation
  • Allosteric Site*
  • Binding Sites
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • Ligands