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Merget B.,Heidelberg Innovation | Turk S.,Heidelberg Innovation | Eid S.,Heidelberg Innovation | Rippmann F.,Merck KGaA | Fulle S.,Heidelberg Innovation
Journal of Medicinal Chemistry | Year: 2017

Kinome-wide screening would have the advantage of providing structure-activity relationships against hundreds of targets simultaneously. Here, we report the generation of ligand-based activity prediction models for over 280 kinases by employing Machine Learning methods on an extensive data set of proprietary bioactivity data combined with open data. High quality (AUC > 0.7) was achieved for ∼200 kinases by (1) combining open with proprietary data, (2) choosing Random Forest over alternative tested Machine Learning methods, and (3) balancing the training data sets. Tests on left-out and external data indicate a high value for virtual screening projects. Importantly, the derived models are evenly distributed across the kinome tree, allowing reliable profiling prediction for all kinase branches. The prediction quality was further improved by employing experimental bioactivity fingerprints of a small kinase subset. Overall, the generated models can support various hit identification tasks, including virtual screening, compound repurposing, and the detection of potential off-targets. © 2016 American Chemical Society.

Nasr T.,Helwan University | Bondock S.,Mansoura University | Bondock S.,King Khalid University | Eid S.,Heidelberg Innovation
European Journal of Medicinal Chemistry | Year: 2014

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. In this context, new functionalized thiophene, acrylamide, arylhydrazone, pyrazole and pyridone derivatives bearing sulfisoxazole moiety were designed, synthesized and evaluated for their in vitro antibacterial and antifungal activities. Among the synthesized compounds, thiophene 4d and 6-thioglucosylpyridone 17 displayed significant antibacterial activities against Escherichia coli (MIC, 0.007 μg/mL vs gentamycin 1.95 μg/mL) and Bacillis subtilis (MIC, 0.007 μg/mL vs ampicillin 0.24 μg/mL), respectively. Whereas, the pyrazole 6 showed the highest antifungal activity against Aspergillus fumigates (MIC, 0.03 μg/mL vs amphotericin B 0.12 μg/mL). In general, most of the synthesized compounds exhibited better antimicrobial activities than sulfisoxazole; this might be attributed to the synergistic effect of the sulfonamide and attached heterocyclic moieties as well as the increased lipophilic characters of the synthesized compounds. Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of microbial DHPS enzyme. The results provide important information for the future design of more potent antimicrobial agents. © 2014 Elsevier Ltd. All rights reserved.

Trollmann J.,Kirchhoff Institute for Physics | Trollmann J.,Heidelberg Innovation | Pucci A.,Kirchhoff Institute for Physics | Pucci A.,Center for Advanced Materials | Pucci A.,Heidelberg Innovation
Journal of Physical Chemistry C | Year: 2014

Though data concerning gold's optical properties differ substantially in the literature, the causes for these discrepancies are poorly understood. Surface quality affects the optical response considerably, not only through crystal defects but also through the existing morphology. If optical data analysis is done under the assumption of ideally flat surfaces, the obtained dielectric function or dynamic conductivity and any model parameters represent an effective description that may differ from bulk values according to various preparation conditions. To show this finding in detail, we performed spectroscopic ellipsometry measurements of evaporated gold films in the mid-infrared range, below the onset of the interband transitions, and investigated the sample morphology by means of atomic force microscopy. This study yields effective Drude-model parameters that vary with film morphology over a range that includes most of the published values. Introducing a Bruggeman effective medium to model rough films as a mixture of bulk metal and empty volume makes it possible to find a relation between metal volume fraction and effective plasma frequency. In such a model, the plasma frequency and also the dielectric background resulting from interband transitions decrease as the fraction of empty volume inclusions increases. In contrast, while metal volume fraction is much less influential to relaxation time, the density of the gold crystallites' grain boundaries yields a strong effect. We thus found a plasma frequency, relaxation rate, and dielectric background for the most ideal gold films at room temperature of 7.37(40) × 104 cm-1, 221(1) cm-1, and 9.6(3), respectively. © 2014 American Chemical Society.

Jeltsch A.,University of Stuttgart | Jurkowska R.Z.,Heidelberg Innovation
Nucleic Acids Research | Year: 2016

In mammals, DNA methylation is introduced by the DNMT1, DNMT3A and DNMT3B methyltransferases, which are all large multi-domain proteins containing a catalytic C-terminal domain and an N-terminal part with regulatory functions. Recently, two novel regulatory principles of DNMTs were uncovered. It was shown that their catalytic activity is under allosteric control of N-terminal domains with autoinhibitory function, the RFT and CXXC domains in DNMT1 and the ADD domain in DNMT3. Moreover, targeting and activity of DNMTs were found to be regulated in a concerted manner by interactors and posttranslational modifications (PTMs). In this review, we describe the structures and domain composition of the DNMT1 and DNMT3 enzymes, their DNA binding, catalytic mechanism, multimerization and the processes controlling their stability in cells with a focus on their regulation and chromatin targeting by PTMs, interactors and chromatin modifications. We propose that the allosteric regulation of DNMTs by autoinhibitory domains acts as a general switch for the modulation of the function of DNMTs, providing numerous possibilities for interacting proteins, nucleic acids or PTMs to regulate DNMT activity and targeting. The combined regulation of DNMT targeting and catalytic activity contributes to the precise spatiotemporal control of DNMT function and genome methylation in cells. © 2016 The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Zhang G.,Max Planck Institute for Polymer Research | Moreira L.A.,Max Planck Institute for Polymer Research | Stuehn T.,Max Planck Institute for Polymer Research | Daoulas K.C.,Max Planck Institute for Polymer Research | And 2 more authors.
ACS Macro Letters | Year: 2014

A strategy is developed for generating equilibrated high molecular weight polymer melts described with microscopic detail by sequentially backmapping coarse-grained (CG) configurations. The microscopic test model is generic but retains features like hard excluded volume interactions and realistic melt densities. The microscopic representation is mapped onto a model of soft spheres with fluctuating size, where each sphere represents a microscopic subchain with Nb monomers. By varying Nb, a hierarchy of CG representations at different resolutions is obtained. Within this hierarchy, CG configurations equilibrated with Monte Carlo at low resolution are sequentially fine-grained into CG melts described with higher resolution. A Molecular Dynamics scheme is employed to slowly introduce the microscopic details into the latter. All backmapping steps involve only local polymer relaxation; thus, the computational efficiency of the scheme is independent of molecular weight, being just proportional to system size. To demonstrate the robustness of the approach, microscopic configurations containing up to n = 1000 chains with polymerization degrees N = 2000 are generated and equilibration is confirmed by monitoring key structural and conformational properties. The extension to much longer chains or branched polymers is straightforward. © 2014 American Chemical Society.

Muller M.,University of Gottingen | Daoulas K.Ch.,University of Gottingen | Daoulas K.Ch.,Max Planck Institute for Polymer Research | Daoulas K.Ch.,Heidelberg Innovation
Physical Review Letters | Year: 2011

The difficulty to study intrinsically slow collective processes by computer simulation of particle models stems from multiple disparate time scales (e.g., stiff bonded interactions versus soft nonbonded interactions). Continuum models, which describe the system by collective variables rather than the coordinates of the individual molecular constituents, often do not suffer from this time-scale problem because the stiff microscopic degrees of freedom have been integrated out. We propose to concurrently couple these two descriptions by a heterogeneous multiscale method. We illustrate the technique by studying the Lifshitz-Slyozov coarsening mechanism in a binary polymer blend using a soft coarse-grained particle model and a Landau-Ginzburg-de Gennes free energy functional, respectively. A speedup of up to two orders of magnitudes is achieved. © 2011 American Physical Society.

Volkamer A.,Heidelberg Innovation | Rarey M.,University of Hamburg
Future Medicinal Chemistry | Year: 2014

The amount of known protein structures is continuously growing, exhibited in over 95,000 3D structures freely available via the PDB. Over the last decade, pharmaceutical research has sparked interest in computationally extracting information from this large data pool, resulting in a homology-driven knowledge transfer from annotated to new structures. Studying protein structures with respect to understanding and modulating their functional behavior means analyzing their centers of action. Therefore, the detection and description of potential binding sites on the protein surface is a major step towards protein classification and assessment. Subsequently, these representations can be incorporated to compare proteins, and to predict their druggability or function. Especially in the context of target identification and polypharmacology, automated tools for large-scale target comparisons are highly needed. In this article, developments for automated structure-based target assessment are reviewed and remaining challenges as well as future perspectives are discussed. © 2014 Future Science Ltd.

Daoulas K.C.,Max Planck Institute for Polymer Research | Daoulas K.C.,Heidelberg Innovation | Muller M.,University of Gottingen
Soft Matter | Year: 2013

The prospects of compressible Self-Consistent Field (SCF) theory schemes for describing structures in amphiphilic membranes are illustrated by considering the thermodynamic stability of hourglass-shaped, hydrophobic connections (stalks) between apposed bilayers. The membranes are represented by a coarse-grained, solvent-free model. We represent the chain architecture by a Gaussian-thread representation of the chain architecture and capture the non-bonded interactions with a functional, which is of third-order in the densities of the hydrophilic and the hydrophobic segments. Using a three dimensional real-space scheme, we study the thermodynamic stability of the stalk with respect to two planar apposing bilayers as a function of membrane tension and molecular asymmetry. The structure and thermodynamics predicted by SCF theory agree very well with particle-based simulations, which include fluctuations. We discuss how the longer-range perturbations of the membrane induced by the stalk can affect thermodynamic properties. This journal is © The Royal Society of Chemistry 2013.

News Article | November 8, 2010
Site: www.finsmes.com

This financing is a formal expansion of the company’s Series C round in October 2009, and brings the total to €46m ($63m) in equity. It was led by three existing investors HBM BioVentures Ltd, Wellington Partners, Gilde Healthcare Partners, with a consortium which included National Technology Enterprises Company, Heidelberg Innovation, and private investors. As also stated by Bob Silverman, CEO of mtm laboratories, the company will use a large component of the proceeds of this financing to fund its United States regulatory trial for CINtec® PLUS Cytology that would support a PMA application. CINtec® PLUS Cytology is a screening and diagnostic tool combining high sensitivity and high specificity for detecting high-grade cervical disease in a single test mtm laboratories operates on a global basis and has subsidiaries in the United States, France, Italy and Spain.

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