Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization

Research output: Contribution to journalJournal articleResearchpeer-review

  • Sebastiaan Kuhne
  • Kooistra, Albert Jelke
  • Reggie Bosma
  • Andrea Bortolato
  • Maikel Wijtmans
  • Henry F. Vischer
  • Jonathan S. Mason
  • Chris De Graaf
  • Iwan J.P. De Esch
  • Rob Leurs

Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number19
Pages (from-to)9047-9061
Number of pages15
Publication statusPublished - 13 Oct 2016
Externally publishedYes

ID: 199352441