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

Standard

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

In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 9047-9061.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Kuhne, S, Kooistra, AJ, Bosma, R, Bortolato, A, Wijtmans, M, Vischer, HF, Mason, JS, De Graaf, C, De Esch, IJP & Leurs, R 2016, 'Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization', Journal of Medicinal Chemistry, vol. 59, no. 19, pp. 9047-9061. https://doi.org/10.1021/acs.jmedchem.6b00981

APA

Kuhne, S., Kooistra, A. J., Bosma, R., Bortolato, A., Wijtmans, M., Vischer, H. F., Mason, J. S., De Graaf, C., De Esch, I. J. P., & Leurs, R. (2016). Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization. Journal of Medicinal Chemistry, 59(19), 9047-9061. https://doi.org/10.1021/acs.jmedchem.6b00981

Vancouver

Kuhne S, Kooistra AJ, Bosma R, Bortolato A, Wijtmans M, Vischer HF et al. Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization. Journal of Medicinal Chemistry. 2016 Oct 13;59(19):9047-9061. https://doi.org/10.1021/acs.jmedchem.6b00981

Author

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. / Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 19. pp. 9047-9061.

Bibtex

@article{5a1d121d48ba4f85ba2d1e6c022a2d03,
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",
year = "2016",
month = oct,
day = "13",
doi = "10.1021/acs.jmedchem.6b00981",
language = "English",
volume = "59",
pages = "9047--9061",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "19",

}

RIS

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

VL - 59

SP - 9047

EP - 9061

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 19

ER -

ID: 199352441