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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biogenic Amines / metabolism*
  • Humans
  • Ligands
  • Mutation
  • Receptors, Biogenic Amine / genetics
  • Receptors, Biogenic Amine / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*


  • Biogenic Amines
  • Ligands
  • Receptors, Biogenic Amine
  • Receptors, G-Protein-Coupled