Publications
Ternary Complex PredictionBayesian Optimization for Ternary Complex Prediction (BOTCP)
Proximity-inducing compounds (PICs) are an emergent drug technology through which a protein of interest (POI), often a drug target, is brought into the vicinity of a second protein which modifies the POI's function, abundance or localisation, giving rise to a therapeutic effect. One of the best-known examples for such compounds are heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). PROTACs reduce the abundance of the target protein by establishing proximity to an E3 ligase which targets the protein towards degradation via the ubiquitin-proteasomal pathway. Design of PROTACs in silico requires the computational prediction of the ternary complex consisting of POI, PROTAC molecule, and the E3 ligase. Here, we present a novel machine learning-based method for predicting PROTAC-mediated ternary complex structures using Bayesian optimization.
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Protein-protein interactionsProtein-protein interaction prediction for targeted protein degradation
Recent developments in machine-learning-based molecular fragment linking have demonstrated the importance of Protein-protein interactions (PPIs) play a fundamental role in various biological functions; thus, detecting PPI sites is essential for understanding diseases and developing new drugs. PPI prediction is of particular relevance for the development of drugs employing targeted protein degradation, as their efficacy relies on the formation of a stable ternary complex involving two proteins. However, experimental methods to detect PPI sites are both costly and time-intensive. In recent years, computer-aided approaches have been developed as screening tools, but these tools are primarily based on sequence information and are therefore limited in their ability to address spatial requirements and have thus far not been applied to targeted protein degradation.
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Linker GenerationDecoupled coordinates for machine learning-based molecular fragment linking
Recent developments in machine-learning-based molecular fragment linking have demonstrated the importance of informing the generation process with structural information specifying the relative orientation of the fragments to be linked.
A significant impact on the quality of the generated linkers is demonstrated numerically. The amount of reliable information within the different types of degrees of freedom is investigated. Ablation studies and an information-theoretical analysis are performed. The presented benefits suggest the application of a complete and decoupled relative coordinate system as a standard good practice in linker design.
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Technology OverviewIdentification of Drug-Target Interactions using Xanthos Match Maker™
In this short whitepaper, we have tried to explain our Xanthos Match Maker™ tool for DTI prediction and virtual screening. Our solution not only can achieve a significant performance on a benchmark dataset but also can provide a reasonable prediction on out-of-distribution data. Moreover, the Celeris One platform can cope with the low amount of input data and extract maximum information from sparse input data.
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Case StudyIdentification of Novel West Nile Virus NS2B/NS3 Protease Warheads
In this whitepaper we showcase the utilities of Xanthos Match Maker™ in rapidly and accurately predicting biomolecular interactions between drug/target pairs. Based on a deep learning approach, the presented drug-repurposing case study has arguably demonstrated promising as well as competitive results.
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A Model for Structured Information Representation in Neural Networks of the Brain
eNeuro, 2020
Michael G. Müller, Christos H. Papadimitriou, Wolfgang Maass and Robert Legenstein
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Drug–excipient interactions in the solid state: The role of different stress factors
Molecular Pharmaceutics, 2017
Gressl C, Brunsteiner M, Davis A, Landis M, Pencheva K, Scrivens G, Sluggett G, Wood G, Gruber-Woelfler H, Khinast J, Paudel A
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Light-assisted small-molecule screening against protein kinases
Nature Chemical Biology, 2015
Álvaro Inglés-Prieto, Eva Reichhart, Markus K Muellner, Matthias Nowak, Sebastian M B Nijman, Michael Grusch & Harald Janovjak
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Prediction of drug-packaging interactions via molecular dynamics (MD) simulations
International Journal of Pharmaceutics, July 2012
Feenstra P, Brunsteiner M, Khinast J
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Dabigatran and Dabigatran Ethyl Ester: Potent Inhibitors of Ribosyldihydronicotinamide Dehydrogenase (NQO2)
Journal of Medicinal Chemistry, 2012
Simon Michaelis, Anett Marais, Anna K. Schrey, Olivia Y. Graebner, Cornelia Schaudt, Michael Sefkow, Friedrich Kroll, Mathias Dreger, Mirko Glinski, Hubert Koester, Rainer Metternich, and Jenny J. Fischer
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Global gene disruption in human cells to assign genes to phenotypes by deep sequencing
Nature Biotechnology, 2011
Jan E Carette, Carla P Guimaraes, Irene Wuethrich, Vincent A Blomen, Malini Varadarajan, Chong Sun, George Bell, Bingbing Yuan, Markus K Muellner, Sebastian M Nijman, Hidde L Ploegh & Thijn R Brummelkamp
178
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Rotation of the exo-Methylene Group of 2-Methyleneglutarate Catalyzed by Coenzyme B12-Dependent 2-Methyleneglutarate Mutase from Clostridium barkeri
Journal of the American Chemical Society, 1996
Christopher H. Edwards, Bernard T. Golding, Friedrich Kroll, Birgitta Beatrix, Gerd Bröker, and Wolfgang Buckel
10
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Rationalizing the diverse reactivity of [1.1.1]propellane through sigma-pi-delocalization
Chemical Science, 2020
Alistair J. Sterling, Alexander B. Dürr, Russell C. Smith, Edward A. Anderson and Fernanda Duarte
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Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry
Journal of Medicinal Chemistry, 2016
Lisa von Kleist, Simon Michaelis, Kathrin Bartho, Olivia Graebner, Marén Schlief, Mathias Dreger, Anna K Schrey, Michael Sefkow, Friedrich Kroll, Hubert Koester, Yan Luo
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Targeting a cell state common to triple-negative breast cancers
Molecular Systems Biology, 2015
Markus K Muellner, Barbara Mair, Yasir Ibrahim, Claudia Kerzendorfer, Hannelore Lechtermann, Claudia Trefzer, Freya Klepsch, , André C Müller, Ernestine Leitner, Sabine Macho-Maschler, Giulio Superti-Furga, Keiryn L Bennett, José Baselga, Uwe Rix, Stefan Kubicek, Jacques Colinge, Violeta Serra, Sebastian MB Nijman
19
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TOPS: A versatile software tool for statistical analysis and visualization of combinatorial gene-gene and gene-drug interaction screens
BMC Bioinformatics, 2014
Markus K Muellner, Gerhard Duernberger, Florian Ganglberger, Claudia Kerzendorfer, Iris Z Uras, Andreas Schoenegger, Klaudia Bagienski, Jacques Colinge & Sebastian MB Nijman
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Capture Compound Mass Spectrometry Sheds Light on the Molecular Mechanisms of Liver Toxicity of Two Parkinson Drugs
Toxicological Sciences, 2010
Jenny J. Fischer, Simon Michaelis, Anna K. Schrey, Olivia Graebner nee Baessler, Mirko Glinski, Mathias Dreger, Friedrich Kroll, Hubert Koester
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Evidence for a Mechanism Involving Transient Fragmentation in Carbon Skeleton Rearrangements Dependent on Coenzyme B12
Angewandte Chemie International, 1995
Dr. Birgitta Beatrix,Dr. Oskar Zelder,Dr. Friedrich K. Kroll,Gissur Örlygsson,Prof. Dr. Bernard T. Golding,Prof. Dr. Wolfgang Buckel
74
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Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes
Chemical Science, 2018
Dimitri F. J. Caputo, Carlos Arroniz, Alexander B. Dürr, James J. Mousseau, Antonia F. Stepan, Steven J. Mansfielda and Edward A. Anderson
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NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation
Oncogene, 2015
M P Licciardello, M K Müllner, G Dürnberger, C Kerzendorfer, B Boidol, C Trefzer, S Sdelci, T Berg, T Penz, M Schuster, C Bock, R Kralovics, G Superti-Furga, J Colinge, S M Nijman & S Kubicek
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Structure based descriptors for the estimation of colloidal interactions and protein aggregation propensities
PLoS One, April 2013
Brunsteiner M, Flock M, Nidetzky B
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A chemical genetic screen reveals a resistance mechanism to PI3K inhibitors in cancer
Nature Chemical Biology, 2012
Markus K Muellner, Iris Z Uras, Bianca V Gapp, Claudia Kerzendorfer, Michal Smida, Hannelore Lechtermann, Nils Craig-Mueller, Jacques Colinge, Gerhard Duernberger, and Sebastian MB Nijman
173
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Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole-and pyrazole-based histone deacetylase probes
Journal of Medicinal Chemistry, July 2011
Neelarapu R, Holzle D, Velaparthi D, Bai H, Brunsteiner M, Blond S, Petukhov P
67
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Are meaningful predictions of toxicological outcomes in clinical trials based on in vitro diagnostics of preclinical drug candidates possible?
Future Medicinal Chemistry, 2010
Friedrich Kroll, Mathias Dreger
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Alkyne(carbene) Complexes: Stabilization of an Intermediate of Carbene Annelation
Angewandte Chemie International, 1992
Prof. Dr. Karl Heinz Dötz, Dr. Thomas Schäfer, Friedrich Kroll, Klaus Harms
40
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