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....

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Autores principales:	Ida Osborn Frandsen, Michael W. Boesgaard, Kimberley Fidom, Alexander S. Hauser, Vignir Isberg, Hans Bräuner-Osborne, Petrine Wellendorph, David E. Gloriam
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/87f8aac272544c70b1de0ff93ba5bde1
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spelling	oai:doaj.org-article:87f8aac272544c70b1de0ff93ba5bde12021-12-02T16:08:21ZIdentification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method10.1038/s41598-017-05058-w2045-2322https://doaj.org/article/87f8aac272544c70b1de0ff93ba5bde12017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05058-whttps://doaj.org/toc/2045-2322Abstract 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.Ida Osborn FrandsenMichael W. BoesgaardKimberley FidomAlexander S. HauserVignir IsbergHans Bräuner-OsbornePetrine WellendorphDavid E. GloriamNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ida Osborn Frandsen Michael W. Boesgaard Kimberley Fidom Alexander S. Hauser Vignir Isberg Hans Bräuner-Osborne Petrine Wellendorph David E. Gloriam Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
description	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.
format	article
author	Ida Osborn Frandsen Michael W. Boesgaard Kimberley Fidom Alexander S. Hauser Vignir Isberg Hans Bräuner-Osborne Petrine Wellendorph David E. Gloriam
author_facet	Ida Osborn Frandsen Michael W. Boesgaard Kimberley Fidom Alexander S. Hauser Vignir Isberg Hans Bräuner-Osborne Petrine Wellendorph David E. Gloriam
author_sort	Ida Osborn Frandsen
title	Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
title_short	Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
title_full	Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
title_fullStr	Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
title_full_unstemmed	Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method
title_sort	identification of histamine h3 receptor ligands using a new crystal structure fragment-based method
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/87f8aac272544c70b1de0ff93ba5bde1
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Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragment-based Method

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