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PMID: 29227473 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature chemical biology ·Vol. 14 ·No. 2 ·2018-00-00 ·Pages 126-134

McCorvy JD, Butler KV, Kelly B, Rechsteiner K, Karpiak J, Betz RM, Kormos BL, Shoichet BK, Dror RO, Jin J, Roth BL

Abstract

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.

MeSH Terms
Aripiprazole/chemistry Crystallography, X-Ray Cyclic AMP/chemistry Drug Design Drug Discovery HEK293 Cells Humans Hydrogen Bonding Indoles/chemistry Kinetics Ligands Molecular Dynamics Simulation Mutation Protein Binding Protein Conformation Receptors, G-Protein-Coupled/chemistry Serine/chemistry Signal Transduction beta-Arrestin 1/chemistry
Chemicals
ARRB1 protein, human Indoles Ligands Receptors, G-Protein-Coupled beta-Arrestin 1 Serine Aripiprazole Cyclic AMP
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
McCorvy John D
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.
Butler Kyle V
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.
Kelly Brendan
Departments of Computer Science and Molecular and Cellular Physiology, Institute for Computational and Mathematical Engineering, and Biophysics Program, Stanford University, Stanford, California, USA.
Rechsteiner Katie
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.
Karpiak Joel
Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, San Francisco, California, USA.
Betz Robin M
Departments of Computer Science and Molecular and Cellular Physiology, Institute for Computational and Mathematical Engineering, and Biophysics Program, Stanford University, Stanford, California, USA.
Kormos Bethany L
Neuroscience and Pain Medicinal Chemistry, Pfizer Worldwide R&D, Cambridge, Massachusetts, USA.
Shoichet Brian K
Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, San Francisco, California, USA.
Dror Ron O
Departments of Computer Science and Molecular and Cellular Physiology, Institute for Computational and Mathematical Engineering, and Biophysics Program, Stanford University, Stanford, California, USA.
Jin Jian ORCID
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.
Roth Bryan L
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.
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Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.2527
Published
2018-00-00
Epub
2017-00-11
Pages
126-134
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC5771956
Subset
IM
Grants
NIMH NIH HHS · U01 MH105892 · United States
NIMH NIH HHS · U19 MH082441 · United States
NINDS NIH HHS · R01 NS100930 · United States
NIMH NIH HHS · R01 MH112205 · United States
NIGMS NIH HHS · T32 GM008294 · United States
NIGMS NIH HHS · R35 GM122481 · United States
NIDDK NIH HHS · U24 DK116195 · United States
NIGMS NIH HHS · R01 GM059957 · United States
Databases
PubChem-Substance
348353604, 348353607, 348353608, 348353609, 348353610, 348353611, 348353612, 348353613, 348353614, 348353605, 348353606
External Links
PubMed source DOI: 10.1038/nchembio.2527 PMC Full Text View journal details
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