Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

RETRACTED ARTICLE: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors

This article was retracted on 01 March 2021

Matters Arising to this article was published on 01 March 2021

This article has been updated

Abstract

Understanding the pharmacological similarity of G protein–coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor–ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR–CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand–residue interactions observed in crystallographically characterized GPCRs. GPCR–CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR–CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Ligand contact map of class A GPCRs.
Figure 2: Comparison matrix of class A GPCR binding site and transmembrane sequence similarities compared to GPCR–CoINPocket.
Figure 3: Organization of class A GPCRs based on GPCR–CoINPocket.
Figure 4: The pharmacological neighborhood of orphan receptors, ACKR3 and GPR37L1.
Figure 5: Screening for GPR37L1 surrogate ligands.

Change history

References

  1. Davenport, A.P. et al. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65, 967–986 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Southern, C. et al. Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J. Biomol. Screen. 18, 599–609 (2013).

    PubMed  Google Scholar 

  3. Jenkins, L. et al. Identification of novel species-selective agonists of the G-protein–coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13. Biochem. J. 432, 451–459 (2010).

    CAS  PubMed  Google Scholar 

  4. Kroeze, W.K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ngo, T. et al. Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br. J. Pharmacol. 173, 2934–2951 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fredriksson, R., Lagerström, M.C., Lundin, L.G. & Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256–1272 (2003).

    CAS  PubMed  Google Scholar 

  7. Schiöth, H.B. & Fredriksson, R. The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen. Comp. Endocrinol. 142, 94–101 (2005).

    PubMed  Google Scholar 

  8. Guba, W. et al. From astemizole to a novel hit series of small-molecule somatostatin 5 receptor antagonists via GPCR affinity profiling. J. Med. Chem. 50, 6295–6298 (2007).

    CAS  PubMed  Google Scholar 

  9. Martin, R.E., Green, L.G., Guba, W., Kratochwil, N. & Christ, A. Discovery of the first nonpeptidic, small-molecule, highly selective somatostatin receptor subtype 5 antagonists: a chemogenomics approach. J. Med. Chem. 50, 6291–6294 (2007).

    CAS  PubMed  Google Scholar 

  10. Scholten, D.J. et al. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165, 1617–1643 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lin, H., Sassano, M.F., Roth, B.L. & Shoichet, B.K. A pharmacological organization of G protein–coupled receptors. Nat. Methods 10, 140–146 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. van der Horst, E. et al. A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization. BMC Bioinformatics 11, 316 (2010).

    PubMed  PubMed Central  Google Scholar 

  13. Surgand, J.S., Rodrigo, J., Kellenberger, E. & Rognan, D. A chemogenomic analysis of the transmembrane binding cavity of human G-protein–coupled receptors. Proteins 62, 509–538 (2006).

    CAS  PubMed  Google Scholar 

  14. Jacoby, E. A novel chemogenomics knowledge-based ligand design strategy—application to G protein-coupled receptors. Mol. Inform. 20, 115–123 (2001).

    CAS  Google Scholar 

  15. Gloriam, D.E., Foord, S.M., Blaney, F.E. & Garland, S.L. Definition of the G protein–coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design. J. Med. Chem. 52, 4429–4442 (2009).

    CAS  PubMed  Google Scholar 

  16. Kufareva, I., Ilatovskiy, A.V. & Abagyan, R. Pocketome: an encyclopedia of small-molecule binding sites in 4D. Nucleic Acids Res. 40, D535–D540 (2012).

    CAS  PubMed  Google Scholar 

  17. Venkatakrishnan, A.J. et al. Molecular signatures of G protein-coupled receptors. Nature 494, 185–194 (2013).

    CAS  PubMed  Google Scholar 

  18. Isberg, V. et al. Generic GPCR residue numbers - aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 36, 22–31 (2015).

    CAS  PubMed  Google Scholar 

  19. Nandigam, R.K., Kim, S., Singh, J. & Chuaqui, C. Position specific interaction dependent scoring technique for virtual screening based on weighted protein–ligand interaction fingerprint profiles. J. Chem. Inf. Model. 49, 1185–1192 (2009).

    CAS  PubMed  Google Scholar 

  20. Marcou, G. & Rognan, D. Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. J. Chem. Inf. Model. 47, 195–207 (2007).

    CAS  PubMed  Google Scholar 

  21. Sokal, R.R. & Michener, C.D. A statistical method for evaluating systematic relationships. Univ. Kans. Sci. Bull. 38, 1409–1438 (1958).

    Google Scholar 

  22. Keiser, M.J. et al. Predicting new molecular targets for known drugs. Nature 462, 175–181 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Modi, M.E. et al. Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole. Neuropsychopharmacology 40, 1856–1865 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bento, A.P. et al. The ChEMBL bioactivity database: an update. Nucleic Acids Res. 42, D1083–D1090 (2014).

    CAS  PubMed  Google Scholar 

  25. Kufareva, I., Katritch, V., Stevens, R.C. & Abagyan, R. Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure 22, 1120–1139 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kufareva, I., Rueda, M., Katritch, V., Stevens, R.C. & Abagyan, R. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure 19, 1108–1126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Thelen, M. & Thelen, S. CXCR7, CXCR4 and CXCL12: an eccentric trio? J. Neuroimmunol. 198, 9–13 (2008).

    CAS  PubMed  Google Scholar 

  28. Min, K.D. et al. Identification of genes related to heart failure using global gene expression profiling of human failing myocardium. Biochem. Biophys. Res. Commun. 393, 55–60 (2010).

    CAS  PubMed  Google Scholar 

  29. Marazziti, D. et al. Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor. Proc. Natl. Acad. Sci. USA 110, 16486–16491 (2013).

    CAS  PubMed  Google Scholar 

  30. Smith, N.J. Drug discovery opportunities at the endothelin B receptor-related orphan G protein–coupled receptors, GPR37 and GPR37L1. Front. Pharmacol. 6, 275 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. Leng, N., Gu, G., Simerly, R.B. & Spindel, E.R. Molecular cloning and characterization of two putative G protein-coupled receptors which are highly expressed in the central nervous system. Brain Res. Mol. Brain Res. 69, 73–83 (1999).

    CAS  PubMed  Google Scholar 

  32. Valdenaire, O. et al. A new family of orphan G protein-coupled receptors predominantly expressed in the brain. FEBS Lett. 424, 193–196 (1998).

    CAS  PubMed  Google Scholar 

  33. Shihoya, W. et al. Activation mechanism of endothelin ETB receptor by endothelin-1. Nature 537, 363–368 (2016).

    CAS  PubMed  Google Scholar 

  34. Coleman, J.L. et al. Metalloprotease cleavage of the N terminus of the orphan G protein-coupled receptor GPR37L1 reduces its constitutive activity. Sci. Signal. 9, ra36 (2016).

    PubMed  Google Scholar 

  35. Ngo, T., Coleman, J.L. & Smith, N.J. Using constitutive activity to define appropriate high-throughput screening assays for orphan G protein-coupled receptors. Methods Mol. Biol. 1272, 91–106 (2015).

    CAS  PubMed  Google Scholar 

  36. Sassano, M.F., Doak, A.K., Roth, B.L. & Shoichet, B.K. Colloidal aggregation causes inhibition of G protein-coupled receptors. J. Med. Chem. 56, 2406–2414 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Rezgaoui, M. et al. The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37. J. Cell Sci. 119, 542–549 (2006).

    CAS  PubMed  Google Scholar 

  38. Civelli, O. et al. G protein-coupled receptor deorphanizations. Annu. Rev. Pharmacol. Toxicol. 53, 127–146 (2013).

    CAS  PubMed  Google Scholar 

  39. Isberg, V. et al. Computer-aided discovery of aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J. Chem. Inf. Model. 54, 1553–1557 (2014).

    CAS  PubMed  Google Scholar 

  40. Liu, C. et al. GPR139, an orphan receptor highly enriched in the habenula and septum, is activated by the essential amino acids L-tryptophan and L-phenylalanine. Mol. Pharmacol. 88, 911–925 (2015).

    CAS  PubMed  Google Scholar 

  41. Huang, X.P. et al. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527, 477–483 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Tagat, J.R. et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg. Med. Chem. Lett. 11, 2143–2146 (2001).

    CAS  PubMed  Google Scholar 

  43. Alexander, S.P. et al. The concise guide to PHARMACOLOGY 2015/16: G protein–coupled receptors. Br. J. Pharmacol. 172, 5744–5869 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kufareva, I. & Abagyan, R. in Homology Modelling: Methods and Protocols Vol. 857 (eds Orry, A.J.W. & Abagyan, R.) Ch. 10 (Humana Press, 2012).

  45. McRobb, F.M., Sahagún, V., Kufareva, I. & Abagyan, R. In silico analysis of the conservation of human toxicity and endocrine disruption targets in aquatic species. Environ. Sci. Technol. 48, 1964–1972 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gonnet, G.H., Cohen, M.A. & Benner, S.A. Exhaustive matching of the entire protein sequence database. Science 256, 1443–1445 (1992).

    CAS  PubMed  Google Scholar 

  47. Abagyan, R., Totrov, M. & Kuznetsov, D. ICM—A new method for protein modeling and design: applications to docking and structure prediction from the distorted native conformation. J. Comput. Chem. 15, 488–506 (1994).

    CAS  Google Scholar 

  48. Paradis, E., Claude, J. & Strimmer, K. APE: analyses of phylogenetics and evolution in R language. Bioinformatics 20, 289–290 (2004).

    CAS  PubMed  Google Scholar 

  49. Abagyan, R., Chen, W. & Kufareva, I. in Computational Approaches to Nuclear Receptors (eds. Cozzini, P. & Kellogg, G.E.) 84–109 (The Royal Society of Chemistry, 2012).

Download references

Acknowledgements

This work was supported in part by an Endeavour Research Fellowship from the Australian Government to T.N., an NHMRC & NHF CJ Martin Fellowship (N.J.S.), NHMRC Program Grants 573732 and 1074386 (R.M.G.), and Australian Postgraduate Awards (T.N. & J.L.J.C.). A.G.S. is supported by NHMRC Early Career Fellowship 1090408. R.A., I.K. and A.V.I. are supported by the NIH Grant R01 GM071872. I.K. is supported by R01 AI118985, R01 GM117424, R21 AI121918 and R21 AI122211. N.J.S. thanks the Mostyn Family Foundation for philanthropic support.

Author information

Authors and Affiliations

Authors

Contributions

T.N., F.M.M., R.A., I.K. and N.J.S. conceived the study; T.N. and I.K. wrote the code for the weighted alignment scores with assistance from A.V.I. and R.A.; A.V.I. generated the ChEMBL data set, which was analyzed by T.N., A.V.I. and I.K.; A.G.S. performed dynamic light scattering experiments and analyzed the data; T.N. and N.J.S. designed and performed reporter gene assay experiments; R.M.G. and J.L.J.C. provided key reagents and ideas and R.P.R. provided the initial transmembrane alignments of all class A GPCRs; N.J.S. provided overall supervision of the project; T.N., I.K. & N.J.S. wrote the manuscript. All authors have provided input and approved the final version of the manuscript.

Corresponding authors

Correspondence to Irina Kufareva or Nicola J Smith.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results and Supplementary Figures 1–7. (PDF 4543 kb)

Supplementary Dataset 1

Pairwise comparison of GPCR–CoINPocket scores between Class A GPCRs. (XLSX 23959 kb)

Supplementary Dataset 2

List of class A G protein–coupled receptors entries in the Pocketome. (XLSX 26281 kb)

Supplementary Dataset 3

Raw pairwise contact strength profiled binding site similarities between class A GPCRs. (XLSX 10 kb)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ngo, T., Ilatovskiy, A., Stewart, A. et al. RETRACTED ARTICLE: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat Chem Biol 13, 235–242 (2017). https://doi.org/10.1038/nchembio.2266

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2266

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing