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Molecular Pharmacology

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Research ArticleArticle

Structure-Based Ligand Discovery Targeting Orthosteric and Allosteric Pockets of Dopamine Receptors

J. Robert Lane, Pavel Chubukov, Wei Liu, Meritxell Canals, Vadim Cherezov, Ruben Abagyan, Raymond C. Stevens and Vsevolod Katritch
Molecular Pharmacology December 2013, 84 (6) 794-807; DOI: https://doi.org/10.1124/mol.113.088054
J. Robert Lane
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Pavel Chubukov
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Wei Liu
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Meritxell Canals
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Vadim Cherezov
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Ruben Abagyan
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Raymond C. Stevens
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Vsevolod Katritch
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, California (P.C., W.L., V.C., R.C.S., V.K.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (J.R.L., M.C.); and Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, California (R.A.)
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Abstract

Small molecules targeting allosteric pockets of G protein–coupled receptors (GPCRs) have a great therapeutic potential for the treatment of neurologic and other chronic disorders. Here we performed virtual screening for orthosteric and putative allosteric ligands of the human dopamine D3 receptor (D3R) using two optimized crystal-structure–based models: the receptor with an empty binding pocket (D3RAPO), and the receptor complex with dopamine (D3RDopa). Subsequent biochemical and functional characterization revealed 14 novel ligands with a binding affinity of better than 10 μM in the D3RAPO candidate list (56% hit rate), and 8 novel ligands in the D3RDopa list (32% hit rate). Most ligands in the D3RAPO model span both orthosteric and extended pockets and behave as antagonists at D3R, with compound 7 showing the highest potency of dopamine inhibition (IC50 = 7 nM). In contrast, compounds identified by the D3RDopa model are predicted to occupy an allosteric site at the extracellular extension of the pocket, and they all lack the anchoring amino group. Compounds targeting the allosteric site display a variety of functional activity profiles, where behavior of at least two compounds (23 and 26) is consistent with noncompetitive allosteric modulation of dopamine signaling in the extracellular signal-regulated kinase 1 and 2 phosphorylation and β-arrestin recruitment assays. The high affinity and ligand efficiency of the chemically diverse hits identified in this study suggest utility of structure-based screening targeting allosteric sites of GPCRs.

Footnotes

    • Received June 19, 2013.
    • Accepted September 10, 2013.
  • J.R.L., P.C., and W.L. contributed equally to this work.

  • The study was supported by National Institutes of Health National Institute of General Medical Sciences Protein Structure Initiative [Grant U54 GM094618] (to R.C.S., R.A., V.C., and V.K.); National Health and Medical Research Council project grant [APP1011920] (to J.R.L.); and The Netherlands Organization for Scientific Research [NWO VENI Grant 863.09.018] (to J.R.L.).

  • dx.doi.org/10.1124/mol.113.088054.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (6)
Molecular Pharmacology
Vol. 84, Issue 6
1 Dec 2013
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Research ArticleArticle

Ligand Screening Targeting Orthosteric and Allosteric Sites

J. Robert Lane, Pavel Chubukov, Wei Liu, Meritxell Canals, Vadim Cherezov, Ruben Abagyan, Raymond C. Stevens and Vsevolod Katritch
Molecular Pharmacology December 1, 2013, 84 (6) 794-807; DOI: https://doi.org/10.1124/mol.113.088054

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Research ArticleArticle

Ligand Screening Targeting Orthosteric and Allosteric Sites

J. Robert Lane, Pavel Chubukov, Wei Liu, Meritxell Canals, Vadim Cherezov, Ruben Abagyan, Raymond C. Stevens and Vsevolod Katritch
Molecular Pharmacology December 1, 2013, 84 (6) 794-807; DOI: https://doi.org/10.1124/mol.113.088054
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