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

TY - JOUR

T1 - Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization

AU - Kuhne, Sebastiaan

AU - Kooistra, Albert J.

AU - Bosma, Reggie

AU - Bortolato, Andrea

AU - Wijtmans, Maikel

AU - Vischer, Henry F.

AU - Mason, Jonathan S.

AU - De Graaf, Chris

AU - De Esch, Iwan J.P.

AU - Leurs, Rob

PY - 2016/10/13

Y1 - 2016/10/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84991287591&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.6b00981

DO - 10.1021/acs.jmedchem.6b00981

M3 - Journal article

C2 - 27643714

AN - SCOPUS:84991287591

SN - 0022-2623

VL - 59

SP - 9047

EP - 9061

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -