A5073065359- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Axon Guidance and Neuronal Signaling
- Protein Structure and Dynamics
- Enzyme Structure and Function
- SARS-CoV-2 and COVID-19 Research
- Fibroblast Growth Factor Research
- Viral Infections and Immunology Research
- Heat shock proteins research
- Metabolomics and Mass Spectrometry Studies
- Bacteriophages and microbial interactions
- Biochemical and Molecular Research
- Kruppel-like factors research
- Viral gastroenteritis research and epidemiology
- Advanced NMR Techniques and Applications
- RNA modifications and cancer
- Cancer Mechanisms and Therapy
- Protein Tyrosine Phosphatases
- Wnt/β-catenin signaling in development and cancer
- PARP inhibition in cancer therapy
- vaccines and immunoinformatics approaches
- Natural product bioactivities and synthesis
- Influenza Virus Research Studies
- X-ray Diffraction in Crystallography
- Advanced Biosensing Techniques and Applications
Goethe University Frankfurt
2016-2025
Institute of Organic Chemistry
2024
National Renewable Energy Laboratory
2024
University of Colorado Boulder
2024
Leibniz-Institute for New Materials
2024
Environmental Energy & Engineering
2024
The University of Adelaide
2024
Imperial College London
2024
Fraunhofer Institute for Translational Medicine and Pharmacology
2024
Merck (Germany)
2024
Abstract The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights need for coordinated research to combat COVID-19. A particularly important aspect is development of medication. In addition viral proteins, structured RNA elements represent a potent alternative as drug targets. search drugs that target requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, worldwide consortium NMR researchers aims...
The correct target: cell division cycle protein 37 (Cdc37) and the heat shock (Hsp90) are molecular chaperones crucial for folding stabilization of kinases including oncogenic kinases. NMR studies show that celastrol, a recently identified triterpene targeting Hsp90, in fact binds to Cdc37 disrupts Cdc37–Hsp90 complex. Celastrol inactivates through thiol-mediated mechanism. Detailed facts importance specialist readers published as "Supporting Information". Such documents peer-reviewed, but...
SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these fold independently, in line with data from vivo ex-vivo structural probing experiments. These contain non-base-paired regions potentially harbor ligand-binding pockets. Here, performed an NMR-based screening poised...
Cardiac vascular diseases, especially acute myocardial infarction (AMI), are one of the leading causes death worldwide. Therefore cardio-specific biomarkers such as cardiac troponin I (cTnI) play an essential role in field diagnostics. In order to enable rapid and accurate measurement cTnI with potential online measurements, a chemiluminescence-based immunosensor is presented proof concept. A flow cell was designed combined sensitive CMOS camera allowing optical readout. addition,...
Polo-like kinase 1 (Plk1) is a central regulator of mitosis and has been validated as target for antitumor therapy. The polo-box domain (PBD) Plk1 regulates its activity mediates the subcellular localization interactions with subset substrates. Functional inhibition PBD by low-molecular weight inhibitors shown to represent viable strategy which inhibit enzyme, while avoiding selectivity issues caused conserved nature ATP binding site. Here, we report structure-activity relationships...
The receptor tyrosine kinase EPHA2 (Ephrin type-A 2) plays important roles in oncogenesis, metastasis, and treatment resistance, yet therapeutic targeting, drug discovery, or investigation of biology is hampered by the lack appropriate inhibitors structural information. Here, we used chemical proteomics to survey 235 clinical for their selectivity identified 24 drugs with submicromolar affinities EPHA2. NMR-based conformational dynamics together nine new cocrystal structures delineated...
Abstract Understanding the conformational sampling of translation-arrested ribosome nascent chain complexes is key to understand co-translational folding. Up now, coupling cysteine oxidation, disulfide bond formation and structure in chains has remained elusive. Here, we investigate eye-lens protein γB-crystallin ribosomal exit tunnel. Using mass spectrometry, theoretical simulations, dynamic nuclear polarization-enhanced solid-state magnetic resonance cryo-electron microscopy, show that...
The process by which researchers from all over the world can apply for projects using EFSL poised to ECBL at EU-OPENSCREEN screening facilities and optimize hits identified through our network of chemistry partners.
Calculations predict that cation−π interactions make an important contribution to protein stability. While there have been some attempts experimentally measure strengths of using peptide model systems, much less experimental data are available for globular proteins. We attempted determine the magnitude Lys with aromatic amino acids in four different proteins (LIVBP, MBP, RBP, and Trx). In each case, was replaced Gln Met. a separate series experiments, acid pair by Leu. Stabilities wild-type...
Abstract The amino acid Pro is more rigid than other naturally occurring acids and, in proteins, lacks an amide hydrogen. To understand the structural and thermodynamic effects of substitutions, it was introduced at 13 different positions four leucine–isoleucine–valine binding protein, maltose ribose thioredoxin. Three protein mutants were characterized by X‐ray crystallography to confirm that no changes had occurred upon mutation. In remaining cases, fluorescence CD spectroscopy used show...
The cell division cycle protein 37 (Cdc37) and the 90-kDa heat shock (Hsp90) are molecular chaperones, which crucial elements in signaling pathway. largest class of client proteins for Cdc37 Hsp90 kinases. catalytic domains these kinases stabilized by Cdc37, their proper folding functioning is dependent on Hsp90. Here, we present x-ray crystal structure 16-kDa middle domain human at 1.88 angstroms resolution this complex with 23-kDa N-terminal based heteronuclear solution state NMR data...
Biophysical parameters can accelerate drug development; e.g., rigid ligands may reduce entropic penalty and improve binding affinity. We studied systematically the impact of ligand rigidification on thermodynamics using a series fasudil derivatives inhibiting protein kinase A by crystallography, isothermal titration calorimetry, nuclear magnetic resonance, molecular dynamics simulations. The varied in their internal degrees freedom but conserve number heteroatoms. Counterintuitively, most...
We report here the nuclear magnetic resonance
Abstract Replication of the coronavirus genome starts with formation viral RNA-containing double-membrane vesicles (DMV) following entry into host cell. The multi-domain nonstructural protein 3 (nsp3) is largest encoded by known and serves as a central component replication transcription machinery. Previous studies demonstrated that highly-conserved C-terminal region nsp3 essential for subcellular membrane rearrangement, yet underlying mechanisms remain elusive. Here we report crystal...
Abstract Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in industry and academia. Fragment become more structure-based to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that availability, immediate long-term, high quality fragment-screening library still beyond reach most academic laboratories. Within iNEXT (Infrastructure for NMR, EM X-rays Translational research),...
SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The increased vaccines, thus necessitating for development new intervention strategies including anti-virals. Within international Covid19-NMR consortium, we have identified binders targeting RNA genome SCoV2. We established protocols production NMR characterization more than 80 % all SCoV2 proteins. Here, performed an screening using a fragment library binding 25 proteins hits also against...
Abstract The ephrin type‐A 2 receptor tyrosine kinase (EPHA2) is involved in the development and progression of various cancer types, including colorectal (CRC). There also evidence that EPHA2 plays a key role resistance to endothelial growth factor (EGFR) monoclonal antibody Cetuximab used clinically CRC. Despite promising pharmacological potential EPHA2, only handful specific inhibitors are currently available. In this concept paper, general strategies for inhibition with molecules low...
Targeting the RNA genome of SARS‐CoV‐2 is a viable option for antiviral drug development. We explored three ligand binding sites core pseudoknot frameshift element. iteratively optimized ligands, based on improved affinities, targeting these and report structural dynamic properties identified sites. Available experimental 3D structures element were compared to SAXS NMR data validate its dominant folding state in solution. In order experimentally map silico predicted sites, assignments...
Targeting the RNA genome of SARS‐CoV‐2 is a viable option for antiviral drug development. We explored three ligand binding sites core pseudoknot frameshift element. iteratively optimized ligands, based on improved affinities, targeting these and report structural dynamic properties identified sites. Available experimental 3D structures element were compared to SAXS NMR data validate its dominant folding state in solution. In order experimentally map silico predicted sites, assignments...
The receptor tyrosine kinase EPHA2 has gained attention as a therapeutic drug target for cancer and infectious diseases. However, research EPHA2-based therapies have been hampered by the lack of selective small-molecule inhibitors. Herein we report synthesis evaluation dedicated inhibitors based on clinical BCR-ABL/SRC inhibitor dasatinib lead structure. We designed hybrid structures previously known binders CHEMBL249097, PD-173955, EPHB4 in order to exploit both ATP pocket entrance well...