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Nat Chem Biol. 2018 Feb;14(2):126-134. doi: 10.1038/nchembio.2527. Epub 2017 Dec 11.

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

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National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina, USA.
Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Departments of Computer Science and Molecular and Cellular Physiology, Institute for Computational and Mathematical Engineering, and Biophysics Program, Stanford University, Stanford, California, USA.
Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, San Francisco, California, USA.
Neuroscience and Pain Medicinal Chemistry, Pfizer Worldwide R&D, Cambridge, Massachusetts, USA.


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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