Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization
Research output: Contribution to journal › Journal article › Research › peer-review
Sebastiaan Kuhne, Albert J. Kooistra, 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.
|Journal||Journal of Medicinal Chemistry|
|Number of pages||15|
|Publication status||Published - 13 Oct 2016|