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

Márton Vass, Sabina Podlewska, Iwan J.P. De Esch, Andrzej J. Bojarski, Rob Leurs, Albert J. Kooistra, Chris De Graaf*

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)3784-3839
Number of pages56
JournalJournal of Medicinal Chemistry
Issue number8
Early online date17 Oct 2018
Publication statusPublished - 25 Apr 2019


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