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ACS Publications. Most Trusted. Most Cited. Most Read
Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data
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    Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data
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    • Márton Vass
      Márton Vass
      Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, 1081HZ Amsterdam, The Netherlands
      More by Márton Vass
    • Sabina Podlewska
      Sabina Podlewska
      Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL31-343 Kraków, Poland
    • Iwan J. P. de Esch
      Iwan J. P. de Esch
      Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, 1081HZ Amsterdam, The Netherlands
    • Andrzej J. Bojarski
      Andrzej J. Bojarski
      Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL31-343 Kraków, Poland
    • Rob Leurs
      Rob Leurs
      Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, 1081HZ Amsterdam, The Netherlands
      More by Rob Leurs
    • Albert J. Kooistra
      Albert J. Kooistra
      Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, 1081HZ Amsterdam, The Netherlands
      Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
    • Chris de Graaf*
      Chris de Graaf
      Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, 1081HZ Amsterdam, The Netherlands
      Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, U.K.
      *E-mail: [email protected]. Phone: +44 (0)1223 949 100.
    Other Access OptionsSupporting Information (1)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 8, 3784–3839
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    https://doi.org/10.1021/acs.jmedchem.8b00836
    Published October 17, 2018
    Copyright © 2018 American Chemical Society

    Abstract

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    The aminergic family of G protein-coupled receptors (GPCRs) plays an important role in various diseases and represents a major drug discovery target class. Structure determination of all major aminergic subfamilies has enabled structure-based ligand design for these receptors. Site-directed mutagenesis data provides an invaluable complementary source of information for elucidating the structural determinants of binding of different ligand chemotypes. The current study provides a comparative analysis of 6692 mutation data points on 34 aminergic GPCR subtypes, covering the chemical space of 540 unique ligands from mutagenesis experiments and information from experimentally determined structures of 52 distinct aminergic receptor–ligand complexes. The integrated analysis enables detailed investigation of structural receptor–ligand interactions and assessment of the transferability of combined binding mode and mutation data across ligand chemotypes and receptor subtypes. An overview is provided of the possibilities and limitations of using mutation data to guide the design of novel aminergic receptor ligands.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00836.

    • Excel file of the aminergic GPCR mutation data (uploaded to Zenodo: 10.5281/zenodo.58104) and GPCRdb: http://gpcrdb.org) and KNIME workflow to analyze the mutation data set; heat maps used for mutation effect prediction, retrospective evaluation and prospective prediction heat maps; PyMOL sessions used to create Figures 3, 7, 10, 13, 16, 19, 20, and 22; PDF versions of Figures 5, 6, 8, 9, 11, 12, 14, 15, 17, and 18 are provided in the Supporting Information. (ZIP)

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    Cited By

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    This article is cited by 51 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 8, 3784–3839
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.8b00836
    Published October 17, 2018
    Copyright © 2018 American Chemical Society

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