A5077192381- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- Synthesis and Biological Evaluation
- Ubiquitin and proteasome pathways
- Chemical Synthesis and Analysis
- Biochemical and Structural Characterization
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Genomics, phytochemicals, and oxidative stress
- Molecular spectroscopy and chirality
- Synthesis and biological activity
- Allergic Rhinitis and Sensitization
- Machine Learning in Materials Science
- Crystallography and molecular interactions
- Food Allergy and Anaphylaxis Research
- Click Chemistry and Applications
- Cancer-related gene regulation
- Bioactive Compounds and Antitumor Agents
- Machine Learning in Bioinformatics
- Advanced Biosensing Techniques and Applications
- Chromatin Remodeling and Cancer
Boehringer Ingelheim (Austria)
2018-2025
Boehringer Ingelheim (Germany)
2023
FZI Research Center for Information Technology
2023
Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR)
2022
Universität Innsbruck
2008-2020
BOKU University
2014-2020
Fuchs (Austria)
2020
University of Cambridge
2014-2019
Unilever (United Kingdom)
2014
Leibniz University Hannover
2014
Abstract Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target E3 ligase, resulting in ubiquitylation proteosome-dependent target. In clinic, oral route administration is option choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally...
Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study
In this study we investigate π-stacking interactions of a variety aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. find that contributes significantly to the and is complemented by varying degree electrostatic interactions. identify geometric preferences minimum energies set 13 5- 6-membered frequently encountered in small drug-like molecules. demonstrate...
The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked shrinkage, the response is usually not durable. Most patients relapse within two years therapy often due acquisition additional EGFR domain that confers resistance TKIs. Crucially, harboring both mutations, T790M and C797S, can no longer be inhibited...
Small modifications of the molecular structure a ligand sometimes cause strong gains in binding affinity to protein target, rendering weakly active chemical series suddenly attractive for further optimization. Our goal this study is better rationalize and predict occurrence such interaction hot-spots receptor sites. To end, we introduce two new concepts into computational description recognition. First, take broader view noncovalent interactions describe protein-ligand with comprehensive set...
Allergy prevalence has increased in industrialized countries. One contributing factor could be pollution, which can cause nitration of allergens exogenously (in the air) or endogenously inflamed lung tissue). We investigated impact on both structural and immunological behavior major birch pollen allergen Bet v 1.0101 to determine whether might a incidence allergy. was nitrated with tetranitromethane. Immune effects were assessed by measuring proliferation specific T-cell lines (TCLs) upon...
BackgroundThe search for intrinsic factors, which account a protein's capability to act as an allergen, is ongoing. Fold stability has been identified molecular feature that affects processing and presentation, thereby influencing antigen's immunologic properties.ObjectiveWe assessed how changes in fold modulate the immunogenicity sensitization capacity of major birch pollen allergen Bet v 1.MethodsBy exploiting exhaustive virtual mutation screening, we generated mutants prototype 1 with...
Significance The transcription factor nuclear kappa B (NF-κB) plays a vital role in cellular immune, stress, and proliferative responses by regulating genes. To maintain correct execution of the genetic program to prevent pathologies (e.g., chronic inflammation), activation NF-κB has be transient precisely controlled. We describe unique inhibitory mechanism that mediates NF-κB–dependent regulation inflammation-associated genes uses arginine methylation RelA subunit protein methyltransferase...
Matrix metalloproteinases play an important role in extracellular matrix remodeling. Excessive activity of these enzymes can be induced by UV light and leads to skin damage, a process known as photoaging. In this study, we investigated the collagenase inhibition potential mycosporine-like amino acids, compounds that have been isolated from marine organisms are photoprotectants against UV-A UV-B. For purpose, commonly used assay was optimized for first time validated terms relationships...
TNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed counteract effect rheumatoid arthritis as well number cancers. In present study we synthesized and evaluated anti-cancer activity novel biscoumarins vitro vivo. Among new compounds, BIHC was found most cytotoxic agent against HepG2 cell line while exhibiting less toxicity toward normal hepatocytes. Furthermore, inhibited proliferation various...
Matched molecular pair analysis (MMPA) has become a major tool for analyzing large chemistry data sets promising chemical transformations. However, the dependence of MMPA predictions on constraints such as number pairs involved, experimental uncertainty, source experiments, and variability true physical effect not yet been described. In this contribution statistical basics judging are analyzed. We illustrate connection between overall statistics individual with detailed comparison average...
Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in sampling extensively profiles the free energy landscape peptidic macrocycles solution. We perform accelerated dynamics simulations to capture diverse ensemble. By applying an energetic cutoff, followed by...
Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these display unusual binding modes involving water displacement from the KAc site. The best compound binds fifth PB1 with a KD 124 nM, SMARCA2B SMARCA4 values 262 417 respectively, displays excellent selectivity over bromodomains other than SMARCA2, SMARCA4.
While CH-π interactions with target proteins are crucial determinants for the affinity of arguably every drug molecule, no method exists to directly measure strength individual in drug-protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate protein-ligand solution. By combining selective amino-acid side-chain labeling 1 H-13 C able identify specific protein protons side-chains engaged aromatic ring systems ligand, based...
Mutations in the gene coding for membrane-bound fatty aldehyde dehydrogenase (FALDH) lead to toxic accumulation of lipid species and development Sjögren–Larsson Syndrome (SLS), a rare disorder characterized by skin defects mental retardation. Here, we present crystallographic structure human FALDH, first model membrane-associated dehydrogenase. The dimeric FALDH displays previously unrecognized element its C-terminal region, ‘gatekeeper’ helix, which extends over adjacent subunit,...
Human BCL-2-associated death promoter (hBAD) is an apoptosis-regulatory protein mediating survival signals to carcinoma cells upon phosphorylation of Ser99, among other residues. Herein, we screened multiple small-molecule databases queried in a Laplacian-modified naive Bayesian-based cheminformatics platform and identified Petasis reaction product as site-specific inhibitor for hBAD phosphorylation. Based on apoptotic efficacy against mammary cells, N-cyclopentyl-3-((4-(2,3-dichlorophenyl)...
We present protease specificity profiling based on quantitative proteomics in combination with proteome-derived peptide libraries. Peptide libraries are generated by endoproteolytic digestion of proteomes without chemical modification primary amines before exposure to a under investigation. After incubation test protease, treated and control differentially isotope-labeled using cost-effective reductive dimethylation. Upon analysis liquid chromatography-tandem mass spectrometry, cleavage...
A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each subpocket based on sequences of cleaved substrates extracted from the MEROPS database. compare our results with known profiles individual proteases and groups (e.g. serine proteases, metallo proteases) reflect them quantitatively. Summation subpocket-wise cleavage contributions yields a measure overall substrate specificity. This total allows...
Nonadditivity in protein–ligand affinity data represents highly instructive structure–activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At same time, nonadditivity is a challenge for both basic SAR analysis as well many ligand-based techniques such Free-Wilson Analysis Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity thus do not work cases. While causes been...
Abstract Protein dynamics is essential to understand protein function and stability, even though rarely investigated as the origin of loss-of-function due genetic variations. Here, we use biochemical, biophysical, cell computational biology tools study two cancer-associated polymorphisms (p.R139W p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes NQO1...