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

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

doi:10.1021/acs.jmedchem.6b00981

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

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^*

^*Corresponding author af dette arbejde

19 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	59
Udgave nummer	19
Sider (fra-til)	9047-9061
Antal sider	15
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.6b00981
Status	Udgivet - 13 okt. 2016
Udgivet eksternt	Ja

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10.1021/acs.jmedchem.6b00981

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Citationsformater

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

abstract = "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.",

author = "Sebastiaan Kuhne and Kooistra, {Albert J.} and Reggie Bosma and Andrea Bortolato and Maikel Wijtmans and Vischer, {Henry F.} and Mason, {Jonathan S.} and {De Graaf}, Chris and {De Esch}, {Iwan J.P.} and Rob Leurs",

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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.

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DO - 10.1021/acs.jmedchem.6b00981

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SN - 0022-2623

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JO - Journal of Medicinal Chemistry

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