A5016675379- Connexins and lens biology
- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Biomedical Text Mining and Ontologies
- Protein Kinase Regulation and GTPase Signaling
- Influenza Virus Research Studies
- Bioinformatics and Genomic Networks
- Cancer Mechanisms and Therapy
- Urinary Bladder and Prostate Research
- Macrophage Migration Inhibitory Factor
- Cytokine Signaling Pathways and Interactions
- Semantic Web and Ontologies
- Peptidase Inhibition and Analysis
- Cellular Mechanics and Interactions
- Biochemical and Molecular Research
- Topic Modeling
- Heat shock proteins research
- Intraocular Surgery and Lenses
- SARS-CoV-2 and COVID-19 Research
- Tuberculosis Research and Epidemiology
- Data Mining Algorithms and Applications
- RNA and protein synthesis mechanisms
- Advanced Fluorescence Microscopy Techniques
- Scientific Computing and Data Management
Fraunhofer Institute for Algorithms and Scientific Computing
2017-2025
KU Leuven
2024
Luxembourg Institute of Health
2024
Centre Hospitalier de Luxembourg
2024
University of Oxford
2024
Fraunhofer Society
2024
Vertex Pharmaceuticals (United States)
2003-2020
Moderna Therapeutics (United States)
2017
University of Auckland
2001-2013
Bioengineering Center
2007
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing cell protection assay identified series azaindole based inhibitors cap-snatching function PB2 subunit influenza A viral polymerase complex. Using bDNA replication (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development novel antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as direct measure activity, we discovered set cyclohexyl carboxylic acid analogues, highlighted...
Pim-1 is an oncogene-encoded serine/threonine kinase primarily expressed in hematopoietic and germ cell lines. was originally identified Maloney murine leukemia virus-induced T-cell lymphomas associated with multiple cellular functions such as proliferation, survival, differentiation, apoptosis, tumorigenesis (Wang, Z., Bhattacharya, N., Weaver, M., Petersen, K., Meyer, Gapter, L., Magnuson, N. S. (2001) J. Vet. Sci. 2, 167–179). The crystal structures of complexed staurosporine adenosine...
ABSTRACT VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for idea occupies 7-methyl GTP (m 7 GTP) cap-binding site PB2. binds domain subunit with K D (dissociation constant) 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC 50 (the concentration compound ensures 50% cell viability an uninfected control) 1.6 in...
The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is key target anticancer drug design. A novel series pyrimidylpyrrole ERK inhibitors has been identified. Discovery conformational change for lead compound 2, when bound to ERK2 relative antitarget GSK3, enabled structure-guided selectivity optimization, which led the discovery 11e, potent, selective, and orally bioavailable inhibitor ERK.
To supplement the hits from a high throughput screen, docking was performed against Pim-1 kinase. Glide augmented with filter to require traditional or aromatic CH··O hydrogen bonds kinase hinge. Four diverse actives, of 96 molecules assayed, had Ki values between 0.091 and 4.5 uM. This gives 14-fold enrichment over earlier HTS run, two crystal structures solved confirmed binding modes predicted by docking.
The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in variety of human cancers. We have identified novel series pyrazolylpyrroles as inhibitors ERK. Aided by the discovery two distinct binding modes for pyrazolylpyrrole scaffold, structure-guided optimization culminated 6p, potent and selective inhibitor
Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), it demonstrates efficacy in rodent models infection. Preclinical vitro vivo studies showed that compound covalently labels liver proteins, presumably via formation reactive metabolite, hence presented potential safety liability. The moiety was identified as being potentially responsible for metabolite...
Pulsed hydrogen-deuterium exchange during refolding was used to probe the protection of backbone amide hydrogens from solvent staphylococcal nuclease Pro117-->Gly variant. The extent for 39 residues determined by two-dimensional proton NMR after 5 ms 10 s. Three kinetic phases are inferred. Modest amides in early intermediate composed two beta-sheets formed local sequence interactions observed a 5-ms period. Protection factors were varying high pH labeling pulse 100 ms. state has modest, yet...
Studies using various MRI techniques have shown that a water-protein concentration gradient exists in the ocular lens. Because this is higher core relative to lens periphery, refractive index established To investigate how profile maintained, bovine lenses were incubated different solutions, and changes ratio monitored proton density weighted (PD-weighted) imaging absence presence of heavy water (D(2)O). Lenses artificial aqueous humor (AAH) maintained steady state gradient, but incubating...
We report a clustering of public human protein kinase structures based on the conformations two structural elements, activation segment and C-helix, revealing three discrete clusters. One cluster includes kinases in catalytically active conformations. Each other clusters contains distinct inactive conformation. Typically, adopt at most one available X-ray structures, implying that is preferred for many kinases. The classification consistent with selectivity profiles several...
The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine that act on substrates associated with cellular motility, morphology, contraction of therapeutic interest in diseases migration contraction, such as hypertension, glaucoma, erectile dysfunction. Beginning compound 4, an inhibitor ROCK1 identified through high-throughput screening, systematic exploration SAR, application structure-based design, led to potent selective ROCK inhibitors. Compound 37 represents significant...
JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide urea substitutions pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at 2-position these analogues. Substitution azaindole ring generated somewhat less potent...
The skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse thickness skin. stage differentiation therefore reflected in positions tissue, providing a convenient axis along which to study signaling events that occur situ during keratinocyte terminal differentiation, over this extended two-week timescale. canonical ERK-MAPK cascade (Raf-1, MEK-1/2 ERK-1/2) has been implicated controlling diverse...
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat variety of autoimmune disorders, including multiple sclerosis, due its role in immune modulation and microglial activation. By minimizing the number hydrogen bond donors while targeting previously uncovered selectivity pocket adjacent ATP binding site PI3Kγ, we discovered series azaisoindolinones selective, brain penetrant inhibitors PI3Kγ. This ultimately led discovery 16, an orally...
Abstract Motivation The COVID-19 pandemic has prompted an impressive, worldwide response by the academic community. In order to support text mining approaches as well data description, linking and harmonization in context of COVID-19, we have developed ontology representing major novel coronavirus (SARS-CoV-2) entities. a strong scope on chemical entities suited for drug repurposing, this is target ongoing therapeutic development. Results comprises 2270 classes concepts 38 987 axioms (2622...
Abstract Objective Healthcare data such as clinical notes are primarily recorded in an unstructured manner. If adequately translated into structured data, they can be utilized for health economics and set the groundwork better individualized patient care. To structure notes, deep-learning methods, particularly transformer-based models like Bidirectional Encoder Representations from Transformers (BERT), have recently received much attention. Currently, biomedical applications focused on...
Guideline questions are typically proposed by experts.
The COVID-19 pandemic has produced an overwhelming volume of research, yet much it remains focused on individual diseases, largely ignoring the complex relationships between comorbidities. Although extensive literature exists both neurodegenerative diseases (NDDs), namely Alzheimer's and Parkinson's, COVID-19, their intersection underexplored. Co-morbidity modeling is essential, as patients, particularly those hospitalized, often present with multiple conditions. This study addresses this...