A5064295295- Liver physiology and pathology
- Computational Drug Discovery Methods
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Protein Structure and Dynamics
- Heat shock proteins research
- Pancreatic and Hepatic Oncology Research
- Pharmacogenetics and Drug Metabolism
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Genetics, Bioinformatics, and Biomedical Research
- Melanoma and MAPK Pathways
- Cell Adhesion Molecules Research
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- Chemical Reactions and Isotopes
- FOXO transcription factor regulation
- Caveolin-1 and cellular processes
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Boron Compounds in Chemistry
- Chemical Synthesis and Analysis
- Eicosanoids and Hypertension Pharmacology
- Cancer and biochemical research
- Protein Kinase Regulation and GTPase Signaling
Merck (Germany)
2014-2025
Takeda (Germany)
2020
Altana (Germany)
2020
Merck Serono (Italy)
2010-2015
Philipps University of Marburg
1999-2003
University of Michigan
2003
Novo Nordisk (Germany)
2003
Accurate ranking of compounds with regards to their binding affinity a protein using computational methods is great interest pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way estimate affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present results large-scale prospective application FEP+ method active drug discovery projects an setting at Merck KGaA,...
Drug-target residence time (τ), one of the main determinants drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in early stages design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for ranking candidates by their and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set 70 diverse drug-like ligands N-terminal domain HSP90α,...
Abstract Purpose: The mesenchymal–epithelial transition factor (c-Met) receptor, also known as hepatocyte growth receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation associated with variety of human malignancies including cancers the lung, kidney, stomach, liver, brain. In this study, we investigated properties two novel compounds developed to selectively inhibit in antitumor therapeutic...
Here we present an evaluation of the binding affinity prediction accuracy free energy calculation method FEP+ on internal active drug discovery projects and a large new public benchmark set.<br>
Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hypermodification of cognate tRNAs, leading to exchange G34 by preQ1 at wobble position anticodon loop. Mutation tgt gene Shigella flexneri results a significant loss pathogenicity bacterium due inefficient translation virulence protein mRNA. Herein, we describe discovery ligand with an unexpected binding mode. On basis this mode, three slightly deviating pharmacophore hypotheses have been derived. Virtual screening based on...
Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding the hinge region of FAK. By accelerated knowledge-based growing approach, essential pharmacophores were added. The establishment highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine...
Abstract Primary activating mutations in KIT (exons 9/11) are key driver alterations about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for unresectable metastatic or recurrent GIST patients, but secondary resistance the domains frequently occur. Currently approved later-line therapies target these incompletely with limited clinical benefit. M4205, kinome-selective was designed to address this...
Residence time and more recently the association rate constant kon are increasingly acknowledged as important parameters for in vivo efficacy safety of drugs. However, their broader consideration drug development is limited by a lack knowledge how to optimize these parameters. In this study on set 176 heat shock protein 90 inhibitors, structure–kinetic relationships, X-ray crystallography, molecular dynamics simulations were combined retrieve concrete scheme rationally slow down on-rates. We...
Targeting allosteric protein sites is a promising approach to interfere selectively with cellular signaling cascades. We have discovered novel class of insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl]piperidin-4-yl}amide (10) was found nanomolar biochemical, micromolar, IGF-1R activity and no relevant interference insulin up 30 μM. The binding site characterized by X-ray crystallographic studies, the structural...
The one-pot, three-component Sonogashira coupling–TMS-deprotection–CuAAC ("click") sequence is the key reaction for rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, imidazole. Subsequently, protective group was readily removed to give corresponding derivatives these tremendously important NH-heterocycles. All compounds have been tested in a broad panel kinase...
The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example targeted therapy for cancer. approval tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under and relapse observed. Several additional inhibitors have been approved; still, there high unmet need with selectivity broad coverage all clinically relevant mutants. An imidazopyridine hit featuring excellent was identified...
The reaction between [{RhCl2(η-C9Me7)}2] and Tl2[7-Ph-8-R-7,8-nido-C2B9H9](R = H or Ph) in CH2Cl2 afforded the heptamethylindenyl carbarhodaboranes 1-Ph-3-(η-C9Me7)-3,1,2-RhC2B9H101 1,2-Ph2-3-(η-C9Me7)-3,1,2-RhC2B9H92, respectively, good yields. 11B NMR chemical shifts of 1 2 showed that they posses closo pseudocloso structures, respectively. Compound was found to be fluctional solution at room temperature via rotation Ph substituent, but cooling below ca. 230 K arrested this process,...
Here we present an evaluation of the binding affinity prediction accuracy free energy calculation method FEP+ on internal active drug discovery projects and a large new public benchmark set.