A5056362309- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Chemical synthesis and alkaloids
- Monoclonal and Polyclonal Antibodies Research
- Biochemical Analysis and Sensing Techniques
- Neurotransmitter Receptor Influence on Behavior
- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- Advanced Proteomics Techniques and Applications
- Diabetes Treatment and Management
- Psychedelics and Drug Studies
- Genomics and Phylogenetic Studies
- Mast cells and histamine
- Genetics, Bioinformatics, and Biomedical Research
- Pancreatic function and diabetes
- Regulation of Appetite and Obesity
- Chemokine receptors and signaling
University of Copenhagen
2011-2019
University of Cambridge
2015
University of Edinburgh
2014
Radboud University Nijmegen
2013
Bio-Prodict (Netherlands)
2013
Radboud University Medical Center
2013
Recent developments in G protein-coupled receptor (GPCR) structural biology and pharmacology have greatly enhanced our knowledge of structure-function relations, helped improve the scientific foundation for drug design studies. The GPCR database, GPCRdb, serves a dual role disseminating enabling new by providing reference data, analysis tools interactive diagrams. This paper highlights features fifth major GPCRdb release: (i) crystal structure browsing, superposition display ligand...
For the past 20 years, GPCRDB (G protein-coupled receptors database; http://www.gpcr.org/7tm/) has been a 'one-stop shop' for G receptor (GPCR)-related data. The contains experimental data on sequences, ligand-binding constants, mutations and oligomers, as well many different types of computationally derived data, such multiple sequence alignments homology models. also provides visualization analysis tools, plus number query systems. In latest release, all alignments, >65 000 models, have...
The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABA(A) and glycine receptor antagonist. In present study, potential in this scaffold explored through synthesis pharmacological characterization series N- O-substituted THAZ analogues. analogues N-Bn-THAZ (3d) O-Bn-THAZ (4d) were found potent agonists human 5-HT(2A) 5-HT(2C) receptors. Judging from an elaborate profiling at numerous other...
GPR139 is an orphan G protein-coupled receptor expressed mainly in the central nervous system. We developed a pharmacophore model based on known surrogate agonists which led us to propose aromatic-containing dipeptides as potential ligands. Upon testing, demonstrated agonism Gq pathway. Next, testing all 20 proteinogenic l-α-amino acids, L-tryptophan and l-phenylalanine were found have EC50 values of 220 320 μM, respectively, making them first putative endogenous for GPR139.
A 5-HT2A receptor model was constructed by homology modeling based on the β2-adrenergic and G protein-bound opsin crystal structures. The transferred into an active conformation agonist ligand a Gαq peptide in four subsequent steered molecular dynamics (MD) simulations. driving force for transformation addition of several known intermolecular interhelical hydrogen bonds enforcing necessary helical rotameric movements. Subsquent MD simulations without constraints confirmed stability activated...
Abstract The metabotropic glutamate receptors have a wide range of modulatory functions in the central nervous system. They are among most highly pursued drug targets, with relevance for several neurological diseases and number allosteric modulators entered clinical trials. However, so far this has not led to marketed drug, largely because difficulties achieving subtype-selective compounds desired properties. Very recently first crystal structures were published transmembrane domain two...
GPR139 is an orphan G protein-coupled receptor that expressed primarily in the brain. Not much known regarding function of GPR139. Recently we have shown activated by amino acids l-tryptophan and l-phenylalanine (EC50 values 220 μM 320 μM, respectively), as well di-peptides comprised aromatic acids. This led us to hypothesize may be peptides. Sequence alignment binding cavities all class A GPCRs, revealed pocket melanocortin 4 similar Based on chemogenomics principle "similar targets bind...
GPR139 is an orphan G protein-coupled receptor expressed in the brain, particular habenula, hypothalamus and striatum. It has therefore been suggested that a possible target for metabolic disorders Parkinson's disease. Several surrogate agonist series have published GPR139. Two by Shi et al. Dvorak included agonists 1a 7c respectively, with potencies ten-nanomolar range. Furthermore, Isberg Liu previously shown tryptophan (Trp) phenylalanine (Phe) can activate hundred-micromolar In this...
GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels hypothalamus and striatum, regions regulating metabolism locomotion, respectively, therefore been suggested as a potential target for obesity Parkinson's disease. The two aromatic amino acids L-Trp L-Phe have proposed putative endogenous agonists, three structurally related benzohydrazide, glycine benzamide, benzotriazine surrogate agonist series published....
Virtual screening offers an efficient alternative to high-throughput in the identification of pharmacological tools and lead compounds. is typically based on matching target structures or ligand pharmacophores commercial in-house compound catalogues. This study provides first proof-of-concept for our recently reported method where are instead constructed inference residue-ligand fragments from crystal structures. We demonstrate its unique utility G protein-coupled receptors, which represent...
Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range psychiatric neurological disorders. There is clinical need for more highly 5-HT2 receptor subtype-selective most attention has been given to phenethylamine class. Conformationally constrained analogs demonstrated that optimal activity free lone pair electrons 2-oxygen must be oriented syn 5-oxygen pairs anti relative ethylamine moiety. Also ethyl linker providing information about...
During 11–12 August 2014, a Protein Bioinformatics and Community Resources Retreat was held at the Wellcome Trust Genome Campus in Hinxton, UK. This meeting brought together principal investigators of several specialized protein resources (such as CAZy, TCDB MEROPS) well those from databases large centres (including UniProt RefSeq). The retreat divided into five sessions: (1) key challenges, (2) represented, (3) best practices for maintenance curation, (4) information flow to data centers...
We report the first pharmacological tool agonist for <italic>in vitro</italic> characterization of orphan receptor GPR132, preliminary structure–activity relationships based on 32 analogs and a suggested binding mode from docking.
Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, cancer. We recently published CCR1, CCR8, CCR5 agonists positive modulators based on a three metal-ion chelator series: 2,2′-bipyridine, 1,10-phenanthroline, 2,2′;6′,2″-terpyridine. Here, we have performed an in-depth structure–activity relationship study tested eight new optimized analogs. Using density functional theory calculations...
Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range psychiatric neurological disorders.There is clinical need for more highly 5-HT 2 receptor subtype-selective most attention has been given to phenethylamine class.Conformationally constrained analogs demonstrated that optimal activity free lone pair electrons 2-oxygen must be oriented syn 5-oxygen pairs anti relative ethylamine moiety.Also ethyl linker providing information about...