A5049958324- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Spectroscopy and Quantum Chemical Studies
- Protein Degradation and Inhibitors
- Advanced Chemical Physics Studies
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Chemical Synthesis and Analysis
- Enzyme Structure and Function
- Metabolism, Diabetes, and Cancer
- Multiple Myeloma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Cancer-related Molecular Pathways
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Cancer, Lipids, and Metabolism
- Advanced Physical and Chemical Molecular Interactions
- Microbial Natural Products and Biosynthesis
- Scientific Research and Discoveries
- Chronic Myeloid Leukemia Treatments
- Thermodynamic properties of mixtures
- Chronic Lymphocytic Leukemia Research
- Peroxisome Proliferator-Activated Receptors
Bayer (Germany)
2015-2025
Université de Lorraine
2016
Boehringer Ingelheim (Germany)
2011-2013
École Polytechnique Fédérale de Lausanne
2007-2011
ETH Zurich
2007-2009
The authors present a method to calculate free energy differences between two states A and B "on the fly" from single molecular dynamics simulation of reference state R. No computer time has be spent on intermediate states. Only one is sampled, i.e., R which designed such that subset phase space important it union parts B. Therefore, an accurate estimate relative can obtained by construction. applied four test systems (dipole inversion, van der Waals interaction perturbation, charge water...
As the free energy of binding a ligand to its target is one crucial optimization parameters in drug design, accurate prediction highly desirable. In present study we have assessed average accuracy calculations for total 92 ligands five different targets. To make this and future larger scale applications possible automated setup procedure. Starting from user defined modes, procedure decides which connect via perturbation based on maximum common substructure criteria produces all necessary...
An approach to non-Markovian system-environment dynamics is described which based on the construction of a hierarchy coupled effective environmental modes that terminated by coupling final member Markovian bath. For an arbitrary environment, linearly subsystem, discretized spectral density replaced series approximate densities involving increasing number modes. This approximants, are constructed analytically in this paper, guarantees accurate representation overall system-plus-bath up times....
The non-Markovian approach developed in the companion paper [Hughes et al., J. Chem. Phys. 131, 024109 (2009)], which employs a hierarchical series of approximate spectral densities, is extended to treatment nonadiabatic dynamics coupled electronic states. We focus on spin-boson-type Hamiltonian including subset system vibrational modes are treated without any approximation, while set bath transformed chain effective and reduced-dimensional space. Only first member subsystem. construction...
An approach to automatically analyze and use the knowledge contained in electronic laboratory notebooks (ELNs) has been developed. Reactions were reduced their reactive center converted a string representation (SMIRKS) which formed basis for reaction classification silico (retro-)synthesis. Of SMIRKS that occurred at least five times, 98% successfully regenerated original product. The extracted rules corresponding reactants span virtual chemical space showed strong dependence on size of...
Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is catalytic methyltransferase reported to monomethylate residues on histone nonhistone proteins. Although several studies uncovered an important role SMYD2 in promoting cancer by methylation, biology far from being fully understood. Utilization highly potent selective chemical...
The calculation of the relative free energies ligand-protein binding, solvation for different compounds, and conformational states a polypeptide is considerable interest in design or selection potential enzyme inhibitors. Since such processes aqueous solution generally comprise energetic entropic contributions from many molecular configurations, adequate sampling relevant parts configurational space required can be achieved through dynamics simulations. Various techniques to obtain converged...
Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor the bromodomain and PHD finger (BRPF) family member BRPF2 TATA box binding protein-associated factors TAF1 TAF1L. These found large chromatin complexes play important roles transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, subsequent structure–activity relationship optimization...
Prioritizing molecules for synthesis is a key role of computational methods within medicinal chemistry. Multiple tools exist ranking molecules, from the cheap and popular molecular docking to more computationally expensive molecular-dynamics (MD)-based methods. It often questioned whether accuracy rigorous justifies higher cost associated calculation time. Here, we compared performance on binding small seven scoring functions five programs, one end-point method (MM/GBSA), two MD-based free...
A recently proposed method to obtain free energy differences for multiple end states from a single simulation of reference state which was called enveloping distribution sampling (EDS) [J. Chem. Phys. 126, 184110 (2007)] is expanded situations where the configuration space densities do not show overlap. It uses Hamiltonian suggested by Han in 1992 [Phys. Lett. 165, 28 (1992)] molecular dynamics implementation. The allows us calculate "on fly" simulation. influence parameters on accuracy and...
Small molecule kinase inhibitors are critical in the modern treatment of cancers, evidenced by existence over 80 FDA-approved small-molecule inhibitors. Unfortunately, intrinsic or acquired resistance, often causing therapy discontinuation, is frequently caused mutations therapeutic target. The advent clinical tumor sequencing has opened additional opportunities for precision oncology to improve patient outcomes pairing optimal therapies with mutation profiles. However, efforts hindered lack...
The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. more accurate and also computationally demanding techniques are the so-called methods which use conformational sampling from molecular dynamics or Monte Carlo simulations generate thermodynamic averages. Two such widely applied integration (TI) recently introduced enveloping distribution (EDS) In both cases energies through alchemical perturbations of one ligand...
Schemes of increasing sophistication for obtaining free energies binding have been developed over the years, where configurational sampling is used to include all-important entropic contributions energies. However, quality results will also depend on accuracy with which intermolecular interactions are computed at each molecular configuration. In this context, energy change associated rearrangement electrons (electronic polarization and charge transfer) upon a very important effect. Classical...
Significance Proteins dynamically shape shift, adopting different three-dimensional structures, called conformations. The conformations fulfill functions and expose binding surfaces to drug molecules aiming inhibit the protein. While structural biology experiments can capture most frequently occurring conformations, those that are more rarely visited very difficult but may be functionally important. Using extensive computer simulations, we discover an undocumented conformation present in all...
We present an automatic adaptive scheme which allows fast optimization of the reference Hamiltonian parameters in enveloping distribution sampling (EDS). Six different variants update have been tested on a condensed phase test system included recurrent deletion and creation complete water molecules water. All six schemes gave accurate free energy estimates with absolute errors up to 1 kJ/mol for worst 0.1 best scheme. Configurational is focused regions where end state difference...
Macrocycles play an increasing role in drug discovery, but their synthesis is often demanding. Computational tools that suggest macrocyclization based on a known binding mode and estimate the affinity of these macrocycles could have substantial impact medicinal chemistry design process. For both tasks, we established workflow with high practical value. five diverse pharmaceutical targets show effect can be calculated robustly accurately. Applying this method to designed by LigMac, search...
Abstract Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most‐studied anticancer targets nowadays. Since discovery druggable allosteric binding site containing a G12C mutation, has been focus attention oncology research. We report here computationally driven approach aimed at identifying novel and selective covalent inhibitors. The workflow involved initial enumeration virtual molecules tailored for site. Tools such as pharmacophore modeling, docking, free‐energy...
Abstract We test the performance of three different reference state Hamiltonians for enveloping distribution sampling (EDS). EDS is an implementation umbrella which allows estimation various free energy differences “on fly” from a single simulation. This achieved by construction state, envelopes regions configuration space important to end states interest. The proposed differ in way barriers separating these are reduced. system consisted 17 disubstituted benzenes water and complex with...
SMYD3 (SET and MYND domain-containing protein 3) is a lysine methyltransferase that was initially described as an H3K4 involved in transcriptional regulation. has been reported to methylate regulate several nonhistone proteins relevant cancer, including mitogen-activated kinase 2 (MAP3K2), vascular endothelial growth factor receptor 1 (VEGFR1), the human epidermal (HER2). In addition, overexpression of linked poor prognosis certain cancers, suggesting potential oncogene attractive cancer...
PIP4K2A is an insufficiently studied type II lipid kinase that catalyzes the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P2). The involvement PIP4K2A/B in cancer has been suggested, particularly context p53 mutant/null tumors. depletion shown to induce tumor growth inhibition, possibly due hyperactivation AKT and reactive oxygen species-mediated apoptosis. Herein, we report identification novel potent highly selective inhibitors...