A5078167510- Ion channel regulation and function
- Computational Drug Discovery Methods
- Pharmacological Receptor Mechanisms and Effects
- Phenothiazines and Benzothiazines Synthesis and Activities
- Histone Deacetylase Inhibitors Research
- Pharmacological Effects of Natural Compounds
- Cancer therapeutics and mechanisms
- Metabolomics and Mass Spectrometry Studies
- Synthesis and Catalytic Reactions
- Sirtuins and Resveratrol in Medicine
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- Plant-based Medicinal Research
- Analytical Chemistry and Chromatography
- Genomics and Chromatin Dynamics
- PARP inhibition in cancer therapy
- Plant and Biological Electrophysiology Studies
- NF-κB Signaling Pathways
- Model Reduction and Neural Networks
- Antibiotic Resistance in Bacteria
- Evolution and Genetic Dynamics
- RNA and protein synthesis mechanisms
- Synthesis and bioactivity of alkaloids
- Protein Degradation and Inhibitors
- Sulfur-Based Synthesis Techniques
Universität Greifswald
2018-2025
Universitätsmedizin Greifswald
2018-2019
Extensively drug-resistant Klebsiella pneumoniae causing major outbreaks and severe infections has become a significant challenge for health care systems worldwide. Rapid resistance development against last-resort therapeutics like ceftazidime-avibactam is driver the accelerated emergence of such pathogens.
The voltage-gated potassium channel KV7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet requirements of potential drug candidates. Targeting membrane-located requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes lead optimization a highly active compound...
With the release of AlphaFold3, modeling capabilities have expanded beyond protein structure prediction to embrace inherent complexity biomolecular systems, including nucleic acids, ions, small molecules, and their interactions. The increased these assemblies is reflected in input file generation process, presenting a significant hurdle for researchers without advanced computational expertise. While AlphaFold Server comes with user-friendly graphical user interface, it supports only subset...
ABSTRACT The transcription factor B Cell Lymphoma/Leukemia 11B (BCL11B) exerts a bi‐directional function in cancer, with its role as an emerging therapeutic target cancer treatment being particularly intriguing. BCL11B knockouts cultured T cells revealed the acquisition of properties characteristic natural killer cells, hinting at importance innate versus adaptive immune regulation. Our previous studies using Förster Resonance Energy Transfer‐assisted Fluorescence‐Activated Sorting and...
The successful sustainable cultivation of the well-known medicinal plant sundew on rewetted peatlands not only leads to preservation natural populations, but also provides a basis for pharmaceutical use plant. bioactive compounds sundew, flavonoids and naphthoquinones, show biofilm-inhibiting properties against multidrug-resistant, ESBL-producing E. coli strains open up new therapeutic possibilities. This study investigates molecular mechanisms these in biofilm inhibition through proteomic...
The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) tissue discoloration, respectively. While mechanism underlying DILI after prolonged use is not entirely understood, evidence indicates that both are metabolized in an initial step reactive ortho- and/or para-azaquinone diimines or para-quinone diimines, Aiming develop safer alternatives for treatment of pain epilepsy, we attempted separate...
Abstract The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due occasional hepatotoxicity tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise the formation electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in case blue discoloration after prolonged intake retigabine. We examined which structural...
The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies
Puzzling stability: molecular jigsaw pieces of residues characterized in light activity, lipophilicity, stability against oxidation, and hepatotoxicity were combined to yield flupirtine analogue <bold>25b</bold>.
Chiral metabolites of ketamine exerting rapid-onset yet sustained antidepressant effects may be marketed directly in the future, but require chemo- and enantio-selective chromatographic methods for quality assurance control. The behavior S-/R-ketamine, S-/R-norketamine, S-/R-dehydronorketamine, (2R,6R)-/(2S,6S)-hydroxynorketamine supercritical fluid chromatography (SFC) was investigated computationally experimentally with aim identifying problematic pairs enantiomers parameters chiral...
The KV 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain epilepsy. However, as a result adverse reactions, both drugs are currently no longer therapeutic use. flupirtine-induced liver injury linked tissue discolouration do not appear related at first glance; nevertheless, events can be attributed to triaminoaryl scaffold, which is affected by oxidation leading elusive reactive quinone diimine or azaquinone metabolites. Since mechanism...
Abstract Indoles are privileged structures in medicinal and bioorganic chemistry that particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used design aromatic compounds useful interfere with enzymes engaged regulation of substrate acylation status, such sirtuins. However, planarity ring is not necessarily optimal all target enzymes, especially when functionalization side chains required. Replacement flat scaffolds by...
The pharmaceutical industry relies heavily on analytical techniques for identifying and characterizing drug compounds. In this experiment, undergraduate pharmacy students explored the applications of near-infrared spectroscopy analysis its potential patterns relationships among samples. addition, they were introduced to chemometrics field using classical pretreatment data exploration methods. To reduce need expensive instrumental equipment, we have developed a small affordable device based...
In many cases, native states of proteins may be predicted with sufficient accuracy by molecular dynamics simulations (MDSs) modern force fields. Enhanced sampling methods based on MDS are applied for exploring the phase space a protein sequence and to overcome barriers rough conformational energy landscapes. The minimum free state is obtained algorithms providing convergence accuracy. A reliable but computationally very expensive method replica exchange dynamics, modifications this approach...
Abstract Neuronal voltage‐gated potassium channels K V 7.2/K 7.3 are sensitive to small‐molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use flupirtine a pain medication is associated with rare cases drug‐induced liver injury. Thus, safety concerns prevent broader this non‐opioid and non‐steroidal analgesic therapeutic areas unmet medical needs hyperactive bladder or neonatal seizures. With goal studying influences...
Benign by design: active sulfide-analogues of potassium channel opener flupirtine do not form reactive oxidation products<italic>in vitro</italic>.
Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing unique selectivity pocket 2 is a promising strategy towards selective inhibitors. An unrelated approach inhibition with varied tissue distribution targeted drug delivery or spatiotemporal activation by photochemical activation. Azologization two nicotinamide-mimicking lead structures was undertaken to combine both approaches yielded set 33 azobenzenes azopyridines...
An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as gel-like consistency of vitreous body. The model consists a stereolithography 3D-printed flow-through cell with polyacrylamide (PAA) gel its core. This needed be coated an agarose sheath because low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium studied EFC...
KV 7 channel openers have proven their therapeutic value in the treatment of pain as well epilepsy and, moreover, they hold potential to expand into additional indications with unmet medical needs. However, clinically validated but meanwhile discontinued flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected causing adverse drug reactions via formation quinoid oxidation products. Here, we report design synthesis nicotinamide analogs related compounds...
Replica exchange molecular dynamics simulations are one of the most popular approaches to enhance conformational sampling systems. Applications range from protein folding protein–protein or other host–guest interactions, as well binding free energy calculations. While these methods computationally expensive, highly accurate results can be obtained. We recently developed TIGER2hs, an improved version temperature intervals with global replicas (TIGER2) algorithm. This method combines...
ABSTRACT The Krüppel-like transcription factor (KLF) BCL11B is characterized by a wide tissue distribution and crucial functions in key developmental cellular processes, as well various pathologies including cancer HIV infection. Although the basics of activity relevant interactions with other proteins have been uncovered, how this exclusively nuclear protein localizes to its compartment remained unclear. Here, we demonstrate that unlike KLFs, does not require C-terminal DNA-binding domain...