A5088727374- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Genetics, Bioinformatics, and Biomedical Research
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Enzyme Structure and Function
- Quinazolinone synthesis and applications
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- Click Chemistry and Applications
- Synthesis and Biological Evaluation
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- thermodynamics and calorimetric analyses
- Chemical Synthesis and Analysis
- Research on Leishmaniasis Studies
- X-ray Diffraction in Crystallography
- Crystallography and molecular interactions
- Synthesis and Properties of Aromatic Compounds
- Solid-state spectroscopy and crystallography
- Machine Learning in Materials Science
- Protein purification and stability
- Microbial Natural Products and Biosynthesis
- Gene Regulatory Network Analysis
- Fractal and DNA sequence analysis
Schrodinger (United States)
2011-2014
University of Würzburg
2009-2013
Philipps University of Marburg
2005-2007
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,...
Predicting protein–ligand binding free energies is a central aim of computational structure-based drug design (SBDD) — improved accuracy in energy predictions could significantly reduce costs and accelerate project timelines lead discovery optimization. The recent development validation advanced calculation methods represents major step toward this goal. Accurately predicting the relative changes modifications to ligands especially valuable field fragment-based design, since fragment screens...
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly selectively MSI2 competes for its in biochemical assays. treatment mouse human leukemia cells results an increase differentiation apoptosis, inhibition known MSI-targets, shared global gene expression signature similar shRNA depletion MSI2. demonstrates vivo c-MYC reduces disease burden murine...
A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling among most suitable approaches to achieve free predictions, due rigorous statistical framework methodology, correct representation energetics, thorough treatment important degrees freedom in system (including explicit waters). Recent advances methods force fields coupled...
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>
The intrinsic strength of the conjugation and hyperconjugation in 1,3‐butadiene, 1,3‐butadiyne, related compounds was determined by energy decomposition analysis. calculations indicate that π 1,3‐butadiyne is roughly twice as strong hyperconjugative interactions CH CC bonds with multiple are about half between bonds.
DYRK kinases are involved in alternative pre-mRNA splicing as well neuropathological states such Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, biological evaluation of indirubins inhibitors with enhanced selectivity. Modifications bis-indole included polar or acidic functionalities at positions 5' 6' a bromine trifluoromethyl group position 7, affording analogues that possess high activity pronounced specificity. Compound 6i carrying 5'-carboxylate...
Relative binding free energy (RBFE) prediction methods such as perturbation (FEP) are important today for estimating protein–ligand affinities. Significant hardware and algorithmic improvements now allow simulating congeneric series within days. Therefore, RBFE calculations have an enormous potential structure-based drug discovery. As typically only a few representative crystal structures available, other ligands design proposals must be reliably superimposed meaningful results. An observed...
In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, 3,5-diaryl-pyrazin-2-one core was derived from marine sponge alkaloid family hamacanthins. our first series compound 2 discovered as a promising showing strong activity against PDGF-Rβ in kinase assay (IC50 = 0.5 μM). Furthermore, shown to be selective for panel 24 therapeutically relevant protein...
The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of from spermidine and glutathione is an attractive new drug target for development trypanocidal antileishmanial drugs, especially since structural information TryS Leishmania major has become available. Unfortunately, structure was solved without any substrates lacks loop regions that are mechanistically important. This contribution describes docking molecular dynamics simulations led to further insights into and, in...
Die intrinsische Stärke der Konjugation und Hyperkonjugation in 1,3‐Butadien, 1,3‐Butadiin verwandten Verbindungen wurde durch Energiedekompositionsanalyse bestimmt. Rechnungen ergeben, dass die π‐Konjugation im etwa doppelt so stark ist wie 1,3‐Butadien hyperkonjugativen π‐π*‐Wechselwirkungen von C‐H‐ C‐C‐Bindungen mit C‐C‐Mehrfachbindungen halb sind zwischen Mehrfachbindungen.
The model binding site of the cytochrome c peroxidase (CCP) W191G mutant is used to investigate structural and dynamic properties water network at buried cavity using computational methods supported by crystallographic analysis. In particular, differences hydration pattern between uncomplexed state various complexed forms are analyzed as well five complexes CCP with structurally closely related ligands. ability docking programs correctly handle molecules in these systems studied detail. It...
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.
Abstract Quantum chemical calculations using density functional theory at the B3LYP level in combination with relativistic effective core potentials for metals and TZ2P valence basis sets have been carried out elucidating reaction pathways of ethylene addition to MeReO 2 (CH ) ( C1 ). The results are compared our previous studies OsO A1 3 B1 Significant differences found between additions osmium compounds rhenium compound . Seven +C H 4 were studied, but only [2+2] Re,C yielding...
Abstract Mechanisms of protein–carbohydrate recognition attract a lot interest due to their roles in various cellular processes and metabolism disorders. We have performed large‐scale analysis protein structures solved complex with glucose, galactose substituted analogues. found that, on average, sugar molecules establish five hydrogen bonds (HBs) the binding site, including one three HBs bridging water molecules. The free energy contribution direct was estimated using perturbation (FEP+)...
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.
DYRK kinases are involved in alternative pre-mRNA splicing as well neuropathological states such Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, biological evaluation of indirubins inhibitors with enhanced selectivity. Modifications bis-indole included polar or acidic functionalities at positions 5′ 6′ a bromine trifluoromethyl group position 7, affording analogues that possess high activity pronounced specificity. Compound 6i carrying 5′- carboxylate...
We describe a novel method to develop energetically optimized, structure-based pharmacophores for use in rapid silico screening. The combines pharmacophore perception and database screening with protein ligand energetic terms computed by the Glide XP scoring function rank importance of features. derive energy-optimized hypotheses 30 pharmaceutically relevant crystal structures screen assess enrichment active compounds. is compared three other approaches: (1) derived from systematic...
The protozoan parasites of the genus Trypanosoma sp. and Leishmania are responsible for neglected diseases like Chagas’ disease, African sleeping sickness or Leishmaniasis. trypanothione synthetase (TryS) is an attractive new drug target development trypanocidal antileishmanial drugs [1]. In our virtual screening campaign targeting we used representative protein conformations derived from a computational analysis using molecular dynamics (MD) simulations this key component biosynthesis....
SUMMARY The MUSASHI family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum cancers including acute myeloid leukemia. We found that the small molecule Ro 08–2750 (Ro) directly binds MSI2 competes for its in biochemical assays. treatment mouse human leukemia cells resulted an increase differentiation apoptosis, inhibition known MSI-targets, shared global gene expression signature similar shRNA depletion MSI2. demonstrated vivo c-MYC reduced disease burden murine AML...
In this study, we generated a matched molecular pair dataset of halogen/deshalogen compounds with reliable binding affinity data and structural mode information from public databases. The workflow includes automated system preparation setup free energy perturbation relative calculations. We demonstrate the suitability these datasets to investigate performance mechanics force fields simulation algorithms for purpose in silico predictions lead optimization. Our total 115 pairs show highly...