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Molecular Pharmacology

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Research ArticleArticle

Small Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA Encoded Libraries

Seungkirl Ahn, Biswaranjan Pani, Alem W. Kahsai, Eva K. Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M. Wingler, Paula K. Rambarat, Rishabh K. Simhal, Thomas T. Xu, Lillian D. Sun, Paul J. Shim, Dean P. Staus, Li-Yin Huang, Thomas Franch, Xin Chen and Robert J. Lefkowitz
Molecular Pharmacology May 16, 2018, mol.118.111948; DOI: https://doi.org/10.1124/mol.118.111948
Seungkirl Ahn
1 Duke University Medical Center;
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Biswaranjan Pani
1 Duke University Medical Center;
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Alem W. Kahsai
1 Duke University Medical Center;
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Eva K. Olsen
2 Nuevolution A/S;
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Gitte Husemoen
2 Nuevolution A/S;
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Mikkel Vestrgaard
2 Nuevolution A/S;
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Lei Jin
3 Changzhou University, China;
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Shuai Zhao
3 Changzhou University, China;
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Laura M. Wingler
1 Duke University Medical Center;
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Paula K. Rambarat
1 Duke University Medical Center;
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Rishabh K. Simhal
1 Duke University Medical Center;
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Thomas T. Xu
4 Harvard Medical School;
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Lillian D. Sun
5 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University;
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Paul J. Shim
6 Duke University;
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Dean P. Staus
1 Duke University Medical Center;
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Li-Yin Huang
1 Duke University Medical Center;
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Thomas Franch
2 Nuevolution A/S;
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Xin Chen
3 Changzhou University, China;
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Robert J. Lefkowitz
7 HHMI / Duke University Medical Center
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Abstract

Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small molecule libraries, we have discovered and characterized the first β2AR small molecule positive allosteric modulators (PAMs) - compound-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl) thio)benzamide] and its analogs. We utilized purified human β2ARs, occupied by a high affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded compound-6. It exhibits a low micro-molar affinity for the agonist-occupied β2AR, and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Compound-6 is cooperative with G protein and β-arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the β2AR, and potentiates downstream cAMP production and receptor-recruitment of β-arrestin2 (a.k.a. arrestin3). Compound-6 is specific for the β2AR compared to the closely related β1AR. Structure-activity studies of select compound-6 analogs defined the chemical groups that are critical for its biological activity. We thus introduce the first small molecule PAMs for the β2AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described here establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small molecule allosteric compounds targeting unique conformational states of GPCRs.

  • Allosterism
  • Beta-adrenergic receptors
  • Drug discovery
  • G protein-coupled receptors (GPCRs)
  • High throughput screening
  • Structure-activity relationships
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Research ArticleArticle

Small Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA Encoded Libraries

Seungkirl Ahn, Biswaranjan Pani, Alem W. Kahsai, Eva K. Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M. Wingler, Paula K. Rambarat, Rishabh K. Simhal, Thomas T. Xu, Lillian D. Sun, Paul J. Shim, Dean P. Staus, Li-Yin Huang, Thomas Franch, Xin Chen and Robert J. Lefkowitz
Molecular Pharmacology May 16, 2018, mol.118.111948; DOI: https://doi.org/10.1124/mol.118.111948

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Research ArticleArticle

Small Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA Encoded Libraries

Seungkirl Ahn, Biswaranjan Pani, Alem W. Kahsai, Eva K. Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M. Wingler, Paula K. Rambarat, Rishabh K. Simhal, Thomas T. Xu, Lillian D. Sun, Paul J. Shim, Dean P. Staus, Li-Yin Huang, Thomas Franch, Xin Chen and Robert J. Lefkowitz
Molecular Pharmacology May 16, 2018, mol.118.111948; DOI: https://doi.org/10.1124/mol.118.111948
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