Journal of Medicinal Chemistry p. 9047 - 9061 (2016)
Update date:2022-08-15
Topics:
Kuhne, Sebastiaan
Kooistra, Albert J.
Bosma, Reggie
Bortolato, Andrea
Wijtmans, Maikel
Vischer, Henry F.
Mason, Jonathan S.
De Graaf, Chris
De Esch, Iwan J.P.
Leurs, Rob
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.
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