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A pharmacological organization of G protein–coupled receptors


Protein classification typically uses structural, sequence or functional similarity. Here we introduce an orthogonal method that organizes proteins by ligand similarity, focusing on the class A G-protein–coupled receptor (GPCR) protein family. Comparing a ligand-based dendrogram to a sequence-based one, we identified GPCRs that were distantly linked by sequence but were neighbors by ligand similarity. Experimental testing of the ligands predicted to link three of these new pairs confirmed the predicted association, with potencies ranging from low nanomolar to low micromolar. We also predicted hundreds of non-GPCRs closely related to GPCRs by ligand similarity and confirmed several cases experimentally. Ligand similarities among these targets may reflect the conservation of identical ligands among unrelated receptors, which signal in different time domains. Our method integrates these apparently disparate receptors into chemically coherent circuits and suggests which of these receptors may be targeted by individual ligands.

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Figure 1: Dendrograms of human GPCRs with annotated ligands from ChEMBL.
Figure 2: Dose-response curves of new GPCR cross-activities.
Figure 3: Non-GPCRs (orange) highly related to particular GPCRs by ligand similarity (color code is as in Fig. 1).
Figure 4: Dose-response curves of new GPCR cross-activities with non-GPCRs.


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This work was supported by US National Institutes of Health (NIH) grant GM71896 (to B.K.S. and J. Irwin) and by the National Institutes of Mental Health Psychoactive Drug Screening Program, NIH R01 MH61887, an NIH NIDA Eureka grant and NIH DA017204 (to B.L.R.). We thank E. Gregori-Puigjane, M. Keiser and R. Coleman for reading this manuscript. B.K.S. is grateful to I.D. Kuntz and H. Bourne for illuminating conversations about time domains in molecular signaling.

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Authors and Affiliations



H.L. performed the calculations. M.F.S. performed experiments. B.L.R. reviewed experimental observations. H.L. and B.K.S. drafted the manuscript. M.F.S. and B.L.R. extensively edited the manuscript.

Corresponding authors

Correspondence to Bryan L Roth or Brian K Shoichet.

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Competing interests

B.K.S. is the founder of SeaChange Pharmaceuticals, which uses chemoinformatics for target prediction.

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Lin, H., Sassano, M., Roth, B. et al. A pharmacological organization of G protein–coupled receptors. Nat Methods 10, 140–146 (2013).

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