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RETRACTED ARTICLE: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors

Nature Chemical Biology volume 13, pages 235–242 (2017)Cite this article

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Matters Arising to this article was published on 01 March 2021

A Retraction to this article was published on 01 March 2021

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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.

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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.

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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.

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Authors and Affiliations

  1. Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

    Tony Ngo, James L J Coleman, R Peter Riek, Robert M Graham & Nicola J Smith

  2. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia

    Tony Ngo, Alastair G Stewart, James L J Coleman, Robert M Graham & Nicola J Smith

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA

    Andrey V Ilatovskiy, Fiona M McRobb, Ruben Abagyan & Irina Kufareva

  4. Structural and Computational Biology Division, Molecular, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

    Alastair G Stewart

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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.

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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)

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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

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