Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs


Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid–ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy may facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands.

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Figure 1: Structure-inspired design of indole-aripiprazole hybrid ligands.
Figure 2: Indole-aripiprazole hybrid D2R SFSR.
Figure 3: D2R MD simulations predict EL2 engagement for arrestin bias.
Figure 4: D2 TM5 and EL2 mutants confirm arrestin-bias binding pose.
Figure 5: MD-assisted rational design of arrestin-biased compounds.
Figure 6: Prediction and confirmation of polypharmacological arrestin bias.

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We thank S. Hollingsworth for assistance with simulation analysis and A.J. Venkatakrishnan for assistance with simulation setup. We thank R. Axel at Columbia University for the HTLA cells and M. Bouvier at Université de Montréal for BRET constructs. This work was supported by the National Institutes of Health (NIH) grant U19MH082441 (to B.L.R. and J.J.), R01MH112205 (to B.L.R.), R01NS100930 (to J.J.), the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP; to B.L.R.), the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics (to B.L.R.), the American Cancer Society postdoctoral fellowship PF-14-021-01-CDD (to K.V.B.), by NIH grant GM59957 (to B.K.S.), by Pfizer, Inc. (R.O.D.), by a Terman Faculty Fellowship (to R.O.D.), and by a National Science Foundation Graduate Research Fellowship (to R.M.B.).

Author information

J.D.M. designed experiments, performed mutagenesis, ligand-binding and signaling studies, analyzed the data, and wrote the manuscript. K.V.B. designed and synthesized all ligands, performed analytical chemical analysis and wrote the manuscript. B.K. performed and analyzed MD simulations, used the results to design ligands, and wrote the manuscript. K.R. assisted with mutagenesis and signaling studies. B.K., J.K., and B.L.K. built the D2 homology model. J.K. performed the docking experiments and edited the manuscript. R.M.B. determined ligand parameters and performed preliminary MD simulations. B.K.S. supervised the docking experiments and edited the manuscript. R.O.D. supervised the MD simulation studies and helped prepare the manuscript. J.J. supervised ligand synthesis, designed experiments and edited the manuscript. B.L.R. designed the experiments, was responsible for the overall project strategy and management and prepared the manuscript.

Correspondence to Ron O Dror or Jian Jin or Bryan L Roth.

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McCorvy, J., Butler, K., Kelly, B. et al. Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14, 126–134 (2018).

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