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J Med Chem. 2019 Apr 25;62(8):3784-3839. doi: 10.1021/acs.jmedchem.8b00836. Epub 2018 Nov 27.

Aminergic GPCR-Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data.

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Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS) , VU University Amsterdam , 1081HZ Amsterdam , The Netherlands.
Department of Medicinal Chemistry, Institute of Pharmacology , Polish Academy of Sciences , Smętna 12 , PL31-343 Kraków , Poland.
Department of Drug Design and Pharmacology , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen , Denmark.
Sosei Heptares , Steinmetz Building, Granta Park, Great Abington , Cambridge CB21 6DG , U.K.


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.

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