A5021939092- Receptor Mechanisms and Signaling
- Cannabis and Cannabinoid Research
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Chemical Synthesis and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Neuropeptides and Animal Physiology
- Tryptophan and brain disorders
- Monoclonal and Polyclonal Antibodies Research
- Carbohydrate Chemistry and Synthesis
- Analytical Chemistry and Chromatography
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Machine Learning in Materials Science
- Click Chemistry and Applications
- Neurotransmitter Receptor Influence on Behavior
- Glycosylation and Glycoproteins Research
- Pancreatic function and diabetes
- Adenosine and Purinergic Signaling
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Various Chemistry Research Topics
- Diet and metabolism studies
- Synthesis and Biological Evaluation
- Pharmacogenetics and Drug Metabolism
Roche (Switzerland)
2016-2025
Roche (Sweden)
2023
ETH Zurich
2019
Vifor Pharma (Germany)
2001
Gesundes Kinzigtal (Germany)
1998
Klinikum Frankfurt Höchst
1996
Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione
1996
Technical University of Munich
1991-1995
A computer-based method was developed for rapid and automatic identification of potential "frequent hitters". These compounds show up as hits in many different biological assays covering a wide range targets. scoring scheme elaborated from substructure analysis, multivariate linear nonlinear statistical methods applied to several sets one two-dimensional molecular descriptors. The final model is based on three-layered neural network, yielding predictive Matthews correlation coefficient 0.81....
An extensive fluorine scan of 1,3-oxazines revealed the power fluorine(s) to lower pKa and thereby dramatically change pharmacological profile this class BACE1 inhibitors. The CF3 substituted oxazine 89, a potent highly brain penetrant inhibitor, was able reduce significantly CSF Aβ40 42 in rats at oral doses as low 1 mg/kg. effect long lasting, showing significant reduction even after 24 h. In contrast compound 1b lacking group virtually inactive vivo.
Crystal structure databases offer ample opportunities to derive small molecule conformation preferences, but the derived knowledge is not systematically applied in drug discovery research. We address this gap by a comprehensive and extendable expert system enabling quick assessment of probability given occur. It based on hierarchical torsion patterns that cover large part druglike chemical space. Each pattern has associated frequency histograms generated from CSD PDB data and, histograms,...
The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated leads to lymph node metastasis, suggesting the as a promising therapeutic target. Here, we present crystal structure human CCR7 fused protein Sialidase NanA using data up 2.1 Å resolution. shows ligand Cmp2105 bound an intracellular allosteric binding pocket. A sulfonamide group, characteristic for various ligands, binds patch conserved residues in Gi region...
We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim highlighting those that provide real added value. Our brief accounts encompass broad range and techniques applied variety enzymes receptors. Most these are based on judicious application knowledge about molecular conformations interactions: filling lipophilic pockets gain affinity or selectivity, addition polar substituents,...
Abstract We have demonstrated a prototypical hybrid classical and quantum computational workflow for the quantification of protein–ligand interactions. The combines density matrix embedding theory (DMET) procedure with variational eigensolver (VQE) approach finding molecular electronic ground states. A series ‐secretase (BACE1) inhibitors is rank‐ordered using binding energy differences calculated on latest superconducting transmon (IBM) trapped‐ion (Quantinuum) noisy intermediate scale...
Pharmacological modulation of cannabinoid receptor type 2 (CB2R) holds promise for the treatment neuroinflammatory disorders, such as Alzheimer's disease. Despite importance CB2R, its expression and downstream signaling are insufficiently understood in disease- tissue-specific contexts. Herein, we report first ligand-directed covalent (LDC) labeling CB2R enabled by a novel synthetic strategy application platform reagents. The LDC modification allows visualization study while maintaining...
We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with tailored functional response. The present study discloses structure-based cannabinoid type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction phenyl group at gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity CB2R Kd = 39.1 nM serves as platform synthesis wide variety probes. Notably, first time these fluorescent...
Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels occupancy by small molecules are highly desirable. We the development of LEI121 as a photoreactive probe to study type 2 cannabinoid (CB2R), promising GPCR treat tissue injury inflammatory diseases. is first CB2R-selective bifunctional covalently captures CB2R upon photoactivation. An incorporated alkyne serves ligation handle for introduction reporter groups. enables target engagement studies...
Detection and visualization of the cannabinoid receptor type 2 by a cell-permeable high affinity fluorescent probe platform enables tracing trafficking in live cells zebrafish.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew evidence for a membrane-bound pathway in hormone receptor bindingLuis Moroder, Roberta Romano, Wolfgang Guba, Dale F. Mierke, Horst Kessler, Christine Delporte, Jacques Winand, and Jean ChristopheCite this: Biochemistry 1993, 32, 49, 13551–13559Publication Date (Print):December 14, 1993Publication History Published online1 May 2002Published inissue 14 December...
We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on analysis of homology amino acids defining putative consensus drug binding site SST5R. With this strategy, opioid, histamine, dopamine, and serotonine receptors as closest neighbors The H1 antagonist astemizole was chosen seed structure subsequently transformed into SST5 with nanomolar affinity devoid original target activity.
Advantages like intuitive interpretation, objectivity, general applicability, and its easy, automated calculation make the rmsd (root-mean-squared deviation) measure of choice for investigation accuracy conformational model generators. For comparing conformations a single molecule this is clearly superior method. Single analysis is, however, rare scenario. Typically, are generated huge corporate or external vendor databases high diversity which then further investigated with high-throughput...
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report optimization a weakly active screening hit 1 to potent selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2)...
Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite significance this receptor, researchers lack reliable tools to address questions concerning expression complex mechanism CB2R signaling, especially in cell-type tissue-dependent contexts. Herein, we report first time a versatile ligand platform modular design collection highly specific...
Introduction Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization high-throughput screening hit. The aim this study to characterize the pharmacology, absorption, distribution, metabolism, elimination, toxicity (ADMET)...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCombined Approach of NMR and Molecular Dynamics within a biphasic Membrane Mimetic: Conformation Orientation the Bradykinin Antagonist Hoe 140Wolfgang Guba, Rainer Haessner, Gerd Breipohl, Stefan Henke, Jochen Knolle, Vincenzo Santagada, Horst KesslerCite this: J. Am. Chem. Soc. 1994, 116, 17, 7532–7540Publication Date (Print):August 1, 1994Publication History Published online1 May 2002Published inissue 1 August...
The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 agonists were identified from a high-throughput screen. Lead optimization gave access novel, highly potent, selective (over CB1) triazolopyrimidine derivatives. preliminary structure-activity relationship was established, physicochemical properties in this compound class significantly improved toward better...