Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method. / Frandsen, Ida Osborn; Boesgaard, Michael W; Fidom, Kimberley; Hauser, Alexander S; Isberg, Vignir; Bräuner-Osborne, Hans; Wellendorph, Petrine; Gloriam, David E.

In: Scientific Reports, Vol. 7, No. 1, 4829, 06.07.2017.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Frandsen, IO, Boesgaard, MW, Fidom, K, Hauser, AS, Isberg, V, Bräuner-Osborne, H, Wellendorph, P & Gloriam, DE 2017, 'Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method', Scientific Reports, vol. 7, no. 1, 4829. https://doi.org/10.1038/s41598-017-05058-w

APA

Frandsen, I. O., Boesgaard, M. W., Fidom, K., Hauser, A. S., Isberg, V., Bräuner-Osborne, H., ... Gloriam, D. E. (2017). Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method. Scientific Reports, 7(1), [4829]. https://doi.org/10.1038/s41598-017-05058-w

Vancouver

Frandsen IO, Boesgaard MW, Fidom K, Hauser AS, Isberg V, Bräuner-Osborne H et al. Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method. Scientific Reports. 2017 Jul 6;7(1). 4829. https://doi.org/10.1038/s41598-017-05058-w

Author

Frandsen, Ida Osborn ; Boesgaard, Michael W ; Fidom, Kimberley ; Hauser, Alexander S ; Isberg, Vignir ; Bräuner-Osborne, Hans ; Wellendorph, Petrine ; Gloriam, David E. / Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method. In: Scientific Reports. 2017 ; Vol. 7, No. 1.

Bibtex

@article{6d2a3b4d653d4f0bb8d3e8d70746bf40,
title = "Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method",
abstract = "Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H3 receptor with potencies of 0.7-8.5 μM in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H3 receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H3 receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.",
keywords = "Journal Article",
author = "Frandsen, {Ida Osborn} and Boesgaard, {Michael W} and Kimberley Fidom and Hauser, {Alexander S} and Vignir Isberg and Hans Br{\"a}uner-Osborne and Petrine Wellendorph and Gloriam, {David E}",
year = "2017",
month = "7",
day = "6",
doi = "10.1038/s41598-017-05058-w",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method

AU - Frandsen, Ida Osborn

AU - Boesgaard, Michael W

AU - Fidom, Kimberley

AU - Hauser, Alexander S

AU - Isberg, Vignir

AU - Bräuner-Osborne, Hans

AU - Wellendorph, Petrine

AU - Gloriam, David E

PY - 2017/7/6

Y1 - 2017/7/6

N2 - Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H3 receptor with potencies of 0.7-8.5 μM in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H3 receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H3 receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.

AB - Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H3 receptor with potencies of 0.7-8.5 μM in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H3 receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H3 receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.

KW - Journal Article

U2 - 10.1038/s41598-017-05058-w

DO - 10.1038/s41598-017-05058-w

M3 - Journal article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 4829

ER -

ID: 180729472