A5026691870- Trypanosoma species research and implications
- Synthesis and Biological Evaluation
- Biochemical and Molecular Research
- Research on Leishmaniasis Studies
- Research Data Management Practices
- Cancer therapeutics and mechanisms
- Tuberculosis Research and Epidemiology
- Scientific Computing and Data Management
- Synthesis and biological activity
- Open Education and E-Learning
- Receptor Mechanisms and Signaling
- Environmental Monitoring and Data Management
- Semantic Web and Ontologies
- Distributed and Parallel Computing Systems
- Bioactive Compounds and Antitumor Agents
- Neuropeptides and Animal Physiology
- Library Science and Information Systems
- Diabetes and associated disorders
- Economic and Environmental Valuation
- RNA and protein synthesis mechanisms
- 3D Printing in Biomedical Research
- Mast cells and histamine
- Cloud Computing and Resource Management
- Real-Time Systems Scheduling
- Pluripotent Stem Cells Research
Fraunhofer Institute for Molecular Biology and Applied Ecology
2016-2025
Fraunhofer Institute for Translational Medicine and Pharmacology
2022-2023
The 2016 presidential election was a jarring event for polling in the United States. Preelection polls fueled high-profile predictions that Hillary Clinton's likelihood of winning presidency about 90 percent, with estimates ranging from 71 to over 99 percent. When Donald Trump declared winner presidency, there widespread perception failed. But did fail? And if so, why? Those are among central questions addressed by an American Association Public Opinion Research (AAPOR) ad hoc committee....
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from library natural products, we combined target-based screening on pteridine reductase 1 with phenotypic Trypanosoma brucei for hit identification. Flavonols were identified as hits, and 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. below 10 μM. Four X-ray crystal structures docking studies explained the observed structure–activity relationships. Compound 2...
2-Amino-benzo[d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking crystallography guided design synthesis 42 benzothiazoles. The compounds were assessed Trypanosoma brucei Leishmania major PTR1 inhibition in vitro activity against T. amastigote infantum. We several 2-amino-benzo[d]thiazoles with enzymatic (TbPTR1 IC50 = 0.35 μM; LmPTR1 1.9 μM) low μM antiparasitic brucei. ten...
Pteridine reductase 1 (PTR1) is a key folate pathway enzyme of pathogenic trypanosomatids that reduces biopterin to dihydro- and tetrahydrobiopterin. It promising target for drug design against diseases such as sleeping sickness or leishmaniases. Amongst known PTR1 inhibitors, 2-aminobenzothiazole derivatives the pocket were previously found show good overall toxicity profiles some them display anti-parasite activity. On other hand, compounds containing 3,4-dichlorophenyl moiety,...
The pharmacodynamics of drug-candidates is often optimized by metrics that describe target binding (Kd or Ki value) modulation (IC50). However, these are determined at equilibrium conditions, and consequently information regarding the onset offset engagement lost. Drug-target residence time a measure for lifetime drug-target complex, which has recently been receiving considerable interest, as shown to have prognostic value in vivo efficacy several drugs. In this study, we investigated...
Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated potential previously identified class thiadiazole inhibitors Leishmania major PTR1 activity against Trypanosoma brucei (Tb). solved crystal structures several TbPTR1-inhibitor complexes to guide structure-based design new derivatives. Subsequent synthesis and enzyme- cell-based assays confirm new, mid-micromolar TbPTR1 with low toxicity. In particular, compound 4m,...
Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of with novel mechanisms action are required. The caseinolytic protease subunit P (ClpP) serine conserved among that considered as an interesting drug target. ClpP function involved in protein turnover homeostasis, stress response, virulence other processes. focus this study was identify inhibitors Escherichia coli understand their mode action. A focused library based on diaryl...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective antiparasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure–activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
According to the World Health Organization, more than 1 billion people are at risk of or affected by neglected tropical diseases. Examples such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all prevalent in Africa, South America, India. Our aim within New Medicines for Trypanosomatidic Infections project was use (1) synthetic natural product libraries, (2) screening, (3) a preclinical absorption, distribution, metabolism,...
The development of cell-free high-throughput (HT) methods to screen and select novel lead compounds remains one the key challenges in G protein-coupled receptor (GPCR) drug discovery. Mutational approaches have allowed stabilization GPCRs a purified ligand-free state. increased intramolecular stability overcomes two major drawbacks for usage vitro screening, low density on cells micelles. Here, an HT fluorescence polarization (FP) assay neurotensin type 1 (NTS1) was developed. operates...
Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental cycloguanil as an inhibitor Trypanosoma brucei PTR1 (TbPTR1). A small library derivatives was developed, resulting 1 and 2a having IC50 values 692 186 nM, respectively, toward TbPTR1. Structural analysis revealed that increased potency due combined...
Abstract The embryonic stem cell test (EST) represents the only validated and accepted in vitro system for detection classification of compounds according to their developmental reproductive teratogenic potency. widespread implementation EST, however, particular routine application pharmaceutical development, has not been achieved so far. Several drawbacks still limit high-throughput screening potential drug candidates this format: long assay period, use non-homogeneous viability assays, low...
Target binding kinetics influence the time course of drug effect (pharmacodynamics) both (i) directly, by affecting target occupancy, driven pharmacokinetics drug, competition with endogenous ligands and turnover, (ii) indirectly, signal transduction homeostatic feedback. For dopamine D2 receptor antagonists, it has been hypothesized that fast cause fewer side effects, because part dynamics dopaminergic system is preserved displacement these antagonists.Target antagonists after antagonist...
Foreword by Walter Mears Acknowledgments The Opinion Triangle Press and Public Opinion: Always Linked A Brief History of Polls Emergence Precision Journalism Polling Environment Today Poll: Who Did? Sponsored It? Sampling Questions Timing Is Everything Error Other Sources Pseudo-Polls SLOPS Reporting Polls: Basics Numbers in Context Political Surveys Exit Projections Future Appendix A: World's Shortest Course Statistics B: Twenty Bibliography Index
This report shares the experience during selection, implementation and maintenance phases of an electronic laboratory notebook (ELN) in a public–private partnership project comments on user’s feedback. In particular, we address which time constraints for roll-out ELN exist granted projects benefits and/or restrictions come with out-of-the-box solutions. We discuss several options support functions potential advantages open access Connected to that, identified willingness vivid culture data...
Abstract While awareness of FAIR (Findable, Accessible, Interoperable, and Reusable) principles has expanded across diverse domains, there remains a notable absence impactful narratives regarding the practical application data. This gap is particularly evident in context in-vitro in-vivo experimental studies associated with drug discovery development process. Despite structured nature these data, reliance on classic methods such as spreadsheet-based visualization analysis limited long-term...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective anti-parasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure-activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
This report shares the experience during selection, implementation and maintenance phases of an electronic laboratory notebook (ELN) in a public private partnership project comment on user feedback. In particular, we address which time constraints for roll-out ELN exist granted projects benefits and/or restrictions come with out-of-the-box solutions. We discuss several options support functions potential advantages open access Connected to that, identified willingness vivid culture data...