Gisbert Schneider

Eawag: Das Wasserforschungs-Institut des ETH-Bereichs, Duebendorf, Zurich, Switzerland

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Publications (257)1067.94 Total impact

  • Daniel Reker, Gisbert Schneider
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    ABSTRACT: High-throughput compound screening is time and resource consuming, and considerable effort is invested into screening compound libraries, profiling, and selecting the most promising candidates for further testing. Active-learning methods assist the selection process by focusing on areas of chemical space that have the greatest chance of success while considering structural novelty. The core feature of these algorithms is their ability to adapt the structure-activity landscapes through feedback. Instead of full-deck screening, only focused subsets of compounds are tested, and the experimental readout is used to refine molecule selection for subsequent screening cycles. Once implemented, these techniques have the potential to reduce costs and save precious materials. Here, we provide a comprehensive overview of the various computational active-learning approaches and outline their potential for drug discovery. Copyright © 2014. Published by Elsevier Ltd.
    Drug Discovery Today 12/2014; · 5.96 Impact Factor
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    ABSTRACT: We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition in English 11/2014; · 13.45 Impact Factor
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    ABSTRACT: Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.
    Nature Chemistry 11/2014; 6:1072-1078. · 23.30 Impact Factor
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    ABSTRACT: The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.
    Journal of medicinal chemistry. 09/2014;
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    ABSTRACT: We synthesized a series of vanillin-derived compounds and analyzed them in HeLa cells for their effects on the proliferation of cancer cells. The molecules are derivatives of the lead compound SBE13, a potent inhibitor of the inactive conformation of human polo-like kinase 1 (Plk1). Some of the new designs were able to inhibit cancer cell proliferation to a similar extent as the lead structure. Two of the compounds ((({4-[(6-chloropyridin-3-yl)methoxy]-3-methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine) and (({4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine)) were much stronger in their capacity to reduce HeLa cell proliferation and turned out to potently induce apoptosis and reduce Plk1 kinase activity in vitro.
    Bioorganic & Medicinal Chemistry Letters 09/2014; · 2.33 Impact Factor
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    ABSTRACT: Antimicrobial peptides (AMPs) show remarkable selectivity toward lipid membranes and possess promising antibiotic potential. Their modes of action are diverse and not fully understood, and innovative peptide design strategies are needed to generate AMPs with improved properties. We present a de novo peptide design approach that resulted in new AMPs possessing low-nanomolar membranolytic activities. Thermal analysis revealed an entropy-driven mechanism of action. The study demonstrates sustained potential of advanced computational methods for designing peptides with the desired activity.
    ChemBioChem 09/2014; · 3.06 Impact Factor
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    ABSTRACT: Predicting the macromolecular targets of drug-like molecules has become everyday practice in medicinal chemistry. We present an overview of our recent research activities in the area of polypharmacology-guided drug design. A focus is put on the self-organizing map (SOM) as a tool for compound clustering and visualization. We show how the SOM can be efficiently used for target-panel prediction, drug re-purposing, and the design of focused compound libraries. We also present the concept of virtual organic synthesis in combination with quantitative estimates of ligand-receptor binding, which we used for de novo designing target-selective ligands. We expect these and related approaches to enable the future discovery of personalized medicines.
    CHIMIA International Journal for Chemistry 09/2014; · 1.09 Impact Factor
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    ABSTRACT: Quantifying the properties of macromolecules is a prerequisite for understanding their roles in biochemical processes. One of the less‐explored geometric features of macromolecules is molecular surface irregularity, or ‘roughness’, which can be measured in terms of fractal dimension (D). In this study, we demonstrate that surface roughness correlates with ligand binding potential. We quantified the surface roughnesses of biological macromolecules in a large‐scale survey that revealed D values between 2.0 and 2.4. The results of our study imply that surface patches involved in molecular interactions, such as ligand‐binding pockets and protein‐protein interfaces, exhibit greater local fluctuations in their fractal dimensions than ‘inert’ surface areas. We expect approximately 22 % of a protein’s surface outside of the crystallographically known ligand binding sites to be ligandable. These findings provide a fresh perspective on macromolecular structure and have considerable implications for drug design as well as chemical and systems biology.
    Molecular Informatics 09/2014; 33(9). · 2.01 Impact Factor
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    ABSTRACT: The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure-activity relationship of these aminothiazole-featured pirinixic acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured pirinixic acids we were able to identify the most potent selective PPARγ agonistic pirinixic acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.
    Bioorganic & Medicinal Chemistry Letters 07/2014; · 2.33 Impact Factor
  • Angewandte Chemie 07/2014; 126(27).
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    ABSTRACT: Helicobacter pylori is associated with inflammatory diseases and can cause gastric cancer and mucosa-associated lymphoma. One of the bacterium's key proteins is high temperature requirement A (HpHtrA) protein, an extracellular serine protease that cleaves E-cadherin of gastric epithelial cells, which leads to loss of cell-cell adhesion. Inhibition of HpHtrA may constitute an intervention strategy against H. pylori infection. Guided by the computational prediction of hypothetical ligand binding sites on the surface of HpHtrA, we performed residue mutation experiments that confirmed the functional relevance of an allosteric region. We virtually screened for potential ligands addressing this surface cleft located between the catalytic and PDZ1 domains. Our receptor-based computational method represents protein surface pockets in terms of graph frameworks and retrieves small molecules that satisfy the constraints given by the pocket framework. A new chemical entity was identified that blocked E-cadherin cleavage in vitro by direct binding to HpHtrA, and efficiently blocked pathogen transmigration across the gastric epithelial barrier. A preliminary crystal structure of HpHtrA confirms the validity of a comparative “homology” model of the enzyme, which we used for the computational study. The results of this study demonstrate that addressing orphan protein surface cavities of target macromolecules can lead to new bioactive ligands.
    Chemical Science 06/2014; · 8.60 Impact Factor
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    ABSTRACT: The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.
    Angewandte Chemie International Edition in English 06/2014; · 13.45 Impact Factor
  • Gisbert Schneider
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    ABSTRACT: The computer-assisted generation of new chemical entities (NCEs) has matured into solid technology supporting early drug discovery. Both ligand- and receptor-based methods are increasingly used for designing small lead- and druglike molecules with anticipated multi-target activities. Advanced “polypharmacology” prediction tools are essential pillars of these endeavors. In addition, it has been realized that iterative design-synthesis-test cycles facilitate the rapid identification of NCEs with the desired activity profile. Lab-on-a-chip platforms integrating synthesis, analytics and bioactivity determination and controlled by adaptive, chemistry-driven de novo design software will play an important role for future drug discovery.
    Molecular Informatics. 05/2014;
  • Tiago Rodrigues, Petra Schneider, Gisbert Schneider
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    ABSTRACT: Mikrofluidiksysteme werden für viele Anwendungen im Bereich der chemischen Forschung und Entwicklung eingesetzt, einschließlich der Miniaturisierung von (bio)organischen Synthese- und (Bio)analysemethoden. Gegenwärtig beobachten wir den stetig wachsenden Einsatz von Mikrofluidikverfahren bei der Erforschung neuer chemischer Substanzen. Diese neuen Techniken haben bereits einen spürbaren Einfluss auf die chemische Biologie und molekulare Medizin. In diesem Kurzaufsatz beschreiben wir den aktuellen Stand der Forschung und stellen die jüngsten Fortschritte für die Anwendung von Mikrochip-Reaktoren sowie kleinen und mittelgroßen Coil-Reaktoren in der Synthese bioaktiver Substanzen vor und geben einen Ausblick auf mögliche künftige Anwendungen dieser vielversprechenden Technologie.
    Angewandte Chemie 05/2014;
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    Tiago Rodrigues, Petra Schneider, Gisbert Schneider
    Angewandte Chemie International Edition 05/2014; · 11.34 Impact Factor
  • Tiago Rodrigues, Petra Schneider, Gisbert Schneider
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    ABSTRACT: Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology.
    Angewandte Chemie International Edition 05/2014; · 11.34 Impact Factor
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    ABSTRACT: The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called “mepacrine binding site”. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.
    ChemMedChem 04/2014; · 3.05 Impact Factor
  • Tiago Rodrigues, Gisbert Schneider
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    ABSTRACT: Review: 52 refs.+subrefs.
    ChemInform 04/2014; 45(15).
  • ChemInform 03/2014; 45(12).
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    ABSTRACT: Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure-activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5±0.2μM and 37±2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.
    Bioorganic & medicinal chemistry 03/2014; · 2.82 Impact Factor

Publication Stats

5k Citations
1,067.94 Total Impact Points


  • 2012–2014
    • Eawag: Das Wasserforschungs-Institut des ETH-Bereichs
      Duebendorf, Zurich, Switzerland
    • University of Salzburg
      • Division of Microbiology
      Salzburg, Salzburg, Austria
  • 2010–2014
    • ETH Zurich
      • • Department of Chemistry and Applied Biosciences
      • • Institute of Pharmaceutical Sciences
      Zürich, Zurich, Switzerland
    • Helmholtz Zentrum München
      • Institute of Bioinformatics and Systems Biology
      München, Bavaria, Germany
    • Paul-Ehrlich-Institut
      Langen, Hesse, Germany
  • 2011
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
    • Friedrich Schiller University Jena
      Jena, Thuringia, Germany
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2005–2011
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
    • Heinrich-Heine-Universität Düsseldorf
      • Institute of Neuropathology
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2003–2011
    • Goethe-Universität Frankfurt am Main
      • Institut für Organische Chemie und Chemische Biologie
      Frankfurt am Main, Hesse, Germany
  • 2008–2009
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Columbia University
      New York City, New York, United States
  • 2006
    • Boehringer Ingelheim
      Ingelheim, Rheinland-Pfalz, Germany
  • 2002
    • Universität Freiburg
      • Institute of Biology I
      Freiburg, Lower Saxony, Germany
  • 1998–2002
    • Roche
      • Pharmaceuticals Division
      Basel, BS, Switzerland
  • 1993–1998
    • Freie Universität Berlin
      • • Institute of Experimental Physics
      • • Department of Physics
      Berlín, Berlin, Germany