Explore the words cloud of the DE-ORPHAN project. It provides you a very rough idea of what is the project "DE-ORPHAN" about.
The following table provides information about the project.
|Coordinator Country||Denmark [DK]|
|Total cost||1˙499˙926 €|
|EC max contribution||1˙499˙926 € (100%)|
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
|Duration (year-month-day)||from 2015-05-01 to 2020-04-30|
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|1||KOBENHAVNS UNIVERSITET||DK (KOBENHAVN)||coordinator||1˙499˙926.00|
G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signaling pathways; and provide the first research tool compounds, of orphan peptide receptors.
Determination of physiological agonists (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously.
The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands’ structure-activity relationships important for biological activity and further optimization towards drugs.
The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects.
DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?
|year||authors and title||journal||last update|
Christian Munk, Eshita Mutt, Vignir Isberg, Louise F. Nikolajsen, Janne M. Bibbe, Tilman Flock, Michael A. Hanson, Raymond C. Stevens, Xavier Deupi, David E. Gloriam
An online resource for GPCR structure determination and analysis
published pages: 151-162, ISSN: 1548-7091, DOI: 10.1038/s41592-018-0302-x
|Nature Methods 16/2||2019-11-25|
Simon R. Foster, Alexander S. Hauser, Line Vedel, Ryan T. Strachan, Xi-Ping Huang, Ariana C. Gavin, Sushrut D. Shah, Ajay P. Nayak, Linda M. Haugaard-KedstrÃ¶m, Raymond B. Penn, Bryan L. Roth, Hans BrÃ¤uner-Osborne, David E. Gloriam
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors
published pages: 895-908.e21, ISSN: 0092-8674, DOI: 10.1016/j.cell.2019.10.010
Amanda E. Mackenzie, Tezz Quon, Li-Chiung Lin, Alexander S. Hauser, Laura Jenkins, Asuka Inoue, Andrew B. Tobin, David E. Gloriam, Brian D. Hudson, Graeme Milligan
Receptor selectivity between the G proteins GÎ± 12 and GÎ± 13 is defined by a single leucine-to-isoleucine variation
published pages: 5005-5017, ISSN: 0892-6638, DOI: 10.1096/fj.201801956r
|The FASEB Journal 33/4||2019-11-18|
Anne Cathrine NÃ¸hr, Mohamed A. Shehata, Daniel Palmer, Rina Pokhrel, Maria Vallianou, Simon R. Foster, Patrick R. Gentry, David E. Gloriam, Hans BrÃ¤uner-Osborne
Identification of a novel scaffold for a small molecule GPR139 receptor agonist
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-019-40085-9
|Scientific Reports 9/1||2019-11-18|
Kasper HarpsÃ¸e, Michael W. Boesgaard, Christian Munk, Hans BrÃ¤uner-Osborne, David E. Gloriam
Structural insight to mutation effects uncover a common allosteric site in class C GPCRs
published pages: btw784, ISSN: 1367-4803, DOI: 10.1093/bioinformatics/btw784
Anne Cathrine NÃ¸hr, Willem Jespers, Mohamed A. Shehata, Leonard Floryan, Vignir Isberg, Kirsten Bayer Andersen, Johan Ã…qvist, Hugo GutiÃ©rrez-de-TerÃ¡n, Hans BrÃ¤uner-Osborne, David E. Gloriam
The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-017-01049-z
|Scientific Reports 7/1||2019-05-29|
Xiao-Feng Xiong, Hang Zhang, Christina R. Underwood, Kasper HarpsÃ¸e, Thomas J. Gardella, Mie F. WÃ¶ldike, Michael Mannstadt, David E. Gloriam, Hans BrÃ¤uner-Osborne, Kristian StrÃ¸mgaard
Total synthesis and structureâ€“activity relationship studies of a series of selective G protein inhibitors
published pages: 1035-1041, ISSN: 1755-4330, DOI: 10.1038/nchem.2577
|Nature Chemistry 8/11||2019-05-29|
GÃ¡spÃ¡r PÃ¡ndy-Szekeres, Christian Munk, Tsonko M Tsonkov, Stefan Mordalski, Kasper HarpsÃ¸e, Alexander S Hauser, Andrzej J Bojarski, David E Gloriam
GPCRdb in 2018: adding GPCR structure models and ligands
published pages: D440-D446, ISSN: 0305-1048, DOI: 10.1093/nar/gkx1109
|Nucleic Acids Research 46/D1||2019-05-29|
Alexander S. Hauser, Misty M. Attwood, Mathias Rask-Andersen, Helgi B. SchiÃ¶th, David E. Gloriam
Trends in GPCR drug discovery: new agents, targets and indications
published pages: 829-842, ISSN: 1474-1776, DOI: 10.1038/nrd.2017.178
|Nature Reviews Drug Discovery 16/12||2019-05-29|
Kasper HarpsÃ¸e, Vignir Isberg, Benjamin G. Tehan, Dahlia Weiss, Angela Arsova, Fiona H. Marshall, Hans BrÃ¤uner-Osborne, David E. Gloriam
Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors â€“ A Structural Perspective of Ligands and Mutants
published pages: , ISSN: 2045-2322, DOI: 10.1038/srep13869
|Scientific Reports 5/1||2019-05-29|
Christian Munk, Kasper HarpsÃ¸e, Alexander S Hauser, Vignir Isberg, David E Gloriam
Integrating structural and mutagenesis data to elucidate GPCR ligand binding
published pages: 51-58, ISSN: 1471-4892, DOI: 10.1016/j.coph.2016.07.003
|Current Opinion in Pharmacology 30||2019-05-29|
Anne Cathrine NÃ¸hr, Mohamed A. Shehata, Alexander S. Hauser, Vignir Isberg, Jacek Mokrosinski, I. Sadaf Farooqi, Daniel Sejer Pedersen, David E. Gloriam, Hans BrÃ¤uner-Osborne
The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), Î±-, and Î²-melanocyte stimulating hormone (Î±-MSH, and Î²-MSH), and the conserved core motif HFRW
published pages: , ISSN: 0197-0186, DOI: 10.1016/j.neuint.2016.11.012
C Munk, V Isberg, S Mordalski, K HarpsÃ¸e, K Rataj, A S Hauser, P Kolb, A J Bojarski, G Vriend, D E Gloriam
GPCRdb: the G protein-coupled receptor database - an introduction
published pages: 2195-2207, ISSN: 0007-1188, DOI: 10.1111/bph.13509
|British Journal of Pharmacology 173/14||2019-05-29|
Alexander S. Hauser, Sreenivas Chavali, Ikuo Masuho, Leonie J. Jahn, Kirill A. Martemyanov, David E. Gloriam, M. Madan Babu
Pharmacogenomics of GPCR Drug Targets
published pages: 41-54.e19, ISSN: 0092-8674, DOI: 10.1016/j.cell.2017.11.033
Simon R. Foster, Hans BrÃ¤uner-Osborne
Investigating Internalization and Intracellular Trafficking of GPCRs: New Techniques and Real-Time Experimental Approaches
published pages: , ISSN: , DOI: 10.1007/164_2017_57
|Handbook of Experimental Pharmacology||2019-05-29|
Shehata MA, NÃ¸hr AC, Lissa D, Bisig C, Isberg V, Andersen KB, HarpsÃ¸e K,
BjÃ¶rkling F, BrÃ¤uner-Osborne H, Gloriam DE
Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139
published pages: , ISSN: 2045-2322, DOI: 10.1038/srep36681
Vignir Isberg, Stefan Mordalski, Christian Munk, Krzysztof Rataj, Kasper HarpsÃ¸e, Alexander S. Hauser, Bas Vroling, Andrzej J. Bojarski, Gert Vriend, David E. Gloriam
GPCRdb: an information system for G protein-coupled receptors
published pages: D356-D364, ISSN: 0305-1048, DOI: 10.1093/nar/gkv1178
|Nucleic Acids Research 44/D1||2019-05-29|
Hanna B. Christensen, David E. Gloriam, Daniel Sejer Pedersen, Jack B. Cowland, Niels Borregaard, Hans BrÃ¤uner-Osborne
Applying label-free dynamic mass redistribution assay for studying endogenous FPR1 receptor signalling in human neutrophils
published pages: 72-78, ISSN: 1056-8719, DOI: 10.1016/j.vascn.2017.07.003
|Journal of Pharmacological and Toxicological Methods 88||2019-05-29|
Tilman Flock, Alexander S. Hauser, Nadia Lund, David E. Gloriam, Santhanam Balaji, M. Madan Babu
Selectivity determinants of GPCRâ€“G-protein binding
published pages: 317-322, ISSN: 0028-0836, DOI: 10.1038/nature22070
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