Publications by authors named "Paul Selzer"

42 Publications

Antiparasitics in Animal Health: Quo Vadis?

Trends Parasitol 2021 01 7;37(1):77-89. Epub 2020 Oct 7.

Boehringer Ingelheim Animal Health, Binger Str. 173, 55216 Ingelheim am Rhein, Germany.

Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions.
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http://dx.doi.org/10.1016/j.pt.2020.09.004DOI Listing
January 2021

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Anticoccidial drugs of the livestock industry.

Parasitol Res 2019 Jul 31;118(7):2009-2026. Epub 2019 May 31.

Boehringer Ingelheim Vetmedica GmbH, Ingelheim am Rhein, Germany.

Coccidiosis is a parasitic disease of a wide variety of animals caused by coccidian protozoa. The coccidia are responsible for major economic losses of the livestock industry. For example, the annual cost due to coccidiosis to the global poultry industry has been estimated to exceed US$ 3 billion annually. Currently available drugs for the control of this disease are either polyether ionophorous antibiotics that are derived from fermentation products, or synthetic compounds, produced by chemical synthesis. Unfortunately, no new drugs in either category have been approved for use for decades. Resistance has been documented for all those of the drugs currently employed and therefore the discovery of novel drugs with unique modes of action is imperative if chemotherapy is to remain the principal means to control this disease. This chapter aims to give an overview of the efficacy and mode of action of the current compounds used to control coccidiosis in livestock and provides a brief outlook of research needs for the future.
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http://dx.doi.org/10.1007/s00436-019-06343-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611755PMC
July 2019

How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice.

Assay Drug Dev Technol 2017 Aug/Sep;15(6):239-246. Epub 2017 Aug 11.

1 Novartis Institutes for BioMedical Research (NIBR) , Chemical Biology and Therapeutics (CBT), Basel, Switzerland .

Since 2011, phenotypic screening has been a trend in the pharmaceutical industry as well as in academia. This renaissance was triggered by analyses that suggested that phenotypic screening is a superior strategy to discover first-in-class drugs. Despite these promises and considerable investments, pharmaceutical research organizations have encountered considerable challenges with the approach. Few success stories have emerged in the past 5 years and companies are questioning their investment in this area. In this contribution, we outline what we have learned about success factors and challenges of phenotypic screening. We then describe how our efforts in phenotypic screening have influenced our approach to drug discovery in general. We predict that concepts from phenotypic screening will be incorporated into target-based approaches and will thus remain influential beyond the current trend.
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http://dx.doi.org/10.1089/adt.2017.796DOI Listing
May 2018

Blocking transmission of vector-borne diseases.

Int J Parasitol Drugs Drug Resist 2017 04 30;7(1):90-109. Epub 2017 Jan 30.

ParaC Consulting for Parasitology and Drug Discovery, Altenstein 13, 79685 Haeg-Ehrsberg, Germany. Electronic address:

Vector-borne diseases are responsible for significant health problems in humans, as well as in companion and farm animals. Killing the vectors with ectoparasitic drugs before they have the opportunity to pass on their pathogens could be the ideal way to prevent vector borne diseases. Blocking of transmission might work when transmission is delayed during blood meal, as often happens in ticks. The recently described systemic isoxazolines have been shown to successfully prevent disease transmission under conditions of delayed pathogen transfer. However, if the pathogen is transmitted immediately at bite as it is the case with most insects, blocking transmission becomes only possible if ectoparasiticides prevent the vector from landing on or, at least, from biting the host. Chemical entities exhibiting repellent activity in addition to fast killing, like pyrethroids, could prevent pathogen transmission even in cases of immediate transfer. Successful blocking depends on effective action in the context of the extremely diverse life-cycles of vectors and vector-borne pathogens of medical and veterinary importance which are summarized in this review. This complexity leads to important parameters to consider for ectoparasiticide research and when considering the ideal drug profile for preventing disease transmission.
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http://dx.doi.org/10.1016/j.ijpddr.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302141PMC
April 2017

Isoxazolines: A Novel Chemotype Highly Effective on Ectoparasites.

ChemMedChem 2016 Feb 6;11(3):270-6. Epub 2016 Jan 6.

Boehringer Ingelheim Animal Health GmbH, Binger Straße 173, 55216, Ingelheim am Rhein, Germany.

Efficient control of arthropod ectoparasite infestations has a long-standing history in the agriculture and veterinary sectors, aiming to decrease the parasite burden of affected crops and animals. Ligand-gated chloride channels (LGCCs) modulated by γ-aminobutyric acid (GABA) and glutamate have been identified as suitable molecular targets, and several classes of potent parasiticides have been devised. Due to the increase in cross-resistance and decreased development of new chemical entities, an urgent need for new parasiticides or prevention schemes has emerged. In the last decade, an innovative isoxazoline chemotype appears to offer promise for inhibiting LGCCs with a new mode of action and distinct binding site from that of historical agents. Considerable efforts have focused on optimizing the antiparasitic activity of isoxazolines and may provide the potential for future human use.
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http://dx.doi.org/10.1002/cmdc.201500516DOI Listing
February 2016

Linking phenotypes and modes of action through high-content screen fingerprints.

Assay Drug Dev Technol 2015 Sep 10;13(7):415-27. Epub 2015 Aug 10.

Novartis Institutes for BioMedical Research , Center for Proteomic Chemistry, Basel, Switzerland .

High-content screening (HCS) is a powerful technique for monitoring phenotypic responses to treatments on a cellular and subcellular level. Cellular phenotypes can be characterized by multivariate image readouts such as shape, intensity, or texture. The corresponding feature vectors can thus be defined as HCS fingerprints that serve as a powerful biological compound descriptor. Therefore, clustering or classification of HCS fingerprints across compound treatments allows for the identification of similarities in protein targets or pathways. We developed an HCS-based profiling panel that serves as basis for characterizing the mode of action of compounds. This panel measures phenotypic effects in six different compartments of U-2OS cells, namely the nucleus, the cytoplasm, the endoplasmic reticulum, the Golgi apparatus, and the cytoskeleton. We profiled a set of 2,725 well-annotated compounds and clustered their corresponding HCS fingerprints to establish links between predominant cellular phenotypes and cellular processes and protein targets. We found various different clusters enriched for individual targets (e.g., HDAC, HSP90, TOP1, HMGCR, TUB), signaling pathways (e.g., PIK3/AKT/mTOR), or gene sets associated with diseases (e.g., psoriasis, leukemia). Based on this clustering we were able to identify novel compound-target associations for selected compounds such as a submicromolar inhibitory activity of Silmitasertib (a casein kinase inhibitor) on PI3K and mTOR.
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http://dx.doi.org/10.1089/adt.2015.656DOI Listing
September 2015

Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach.

PLoS Negl Trop Dis 2015 4;9(6):e0003773. Epub 2015 Jun 4.

MSD Animal Health Innovation GmbH, Zur Propstei, Schwabenheim, Germany; Universität Tübingen, Interfakultäres Institut für Biochemie, Tübingen, Germany; Wellcome Trust Centre for Molecular Parasitology, Division of Infection, Immunity and Inflammation, Faculty of Biomedical & Life Sciences, University of Glasgow, Glasgow, United Kingdom.

With the goal to identify novel trypanothione reductase (TR) inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search-based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of <1 μM, were selected for determining the inhibitor constant. In first on parasites assays, three compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 μM.
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http://dx.doi.org/10.1371/journal.pntd.0003773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456413PMC
May 2016

Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.

PLoS Negl Trop Dis 2014 Jun 12;8(6):e2923. Epub 2014 Jun 12.

BFS, Institute for Parasitology, Justus-Liebig-University, Giessen, Germany.

Background: Schistosome parasites cause schistosomiasis, one of the most important infectious diseases worldwide. For decades Praziquantel (PZQ) is the only drug widely used for controlling schistosomiasis. The absence of a vaccine and fear of PZQ resistance have motivated the search for alternatives. Studies on protein kinases (PKs) demonstrated their importance for diverse physiological processes in schistosomes. Among others two Abl tyrosine kinases, SmAbl1 and SmAbl2, were identified in Schistosoma mansoni and shown to be transcribed in the gonads and the gastrodermis. SmAbl1 activity was blocked by Imatinib, a known Abl-TK inhibitor used in human cancer therapy (Gleevec/Glivec). Imatinib exhibited dramatic effects on the morphology and physiology of adult schistosomes in vitro causing the death of the parasites.

Methodology/principal Findings: Here we show modeling data supporting the targeting of SmAbl1/2 by Imatinib. A biochemical assay confirmed that SmAbl2 activity is also inhibited by Imatinib. Microarray analyses and qRT-PCR experiments were done to unravel transcriptional processes influenced by Imatinib in adult schistosomes in vitro demonstrating a wide influence on worm physiology. Surface-, muscle-, gut and gonad-associated processes were affected as evidenced by the differential transcription of e.g. the gynecophoral canal protein gene GCP, paramyosin, titin, hemoglobinase, and cathepsins. Furthermore, transcript levels of VAL-7 and egg formation-associated genes such as tyrosinase 1, p14, and fs800-like were affected as well as those of signaling genes including a ribosomal protein S6 kinase and a glutamate receptor. Finally, a comparative in silico analysis of the obtained microarray data sets and previous data analyzing the effect of a TGFβR1 inhibitor on transcription provided first evidence for an association of TGFβ and Abl kinase signaling. Among others GCP and egg formation-associated genes were identified as common targets.

Conclusions/significance: The data affirm broad negative effects of Imatinib on worm physiology substantiating the role of PKs as interesting targets.
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http://dx.doi.org/10.1371/journal.pntd.0002923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055459PMC
June 2014

Interview with Paul Selzer.

Future Med Chem 2014 Mar;6(3):263-6

Novartis Institutes for Biomedical Research, Basel, Switzerland.

Paul Selzer, a computational chemist at Novartis (Basel, Switzerland), has been part of the computational medicinal chemistry field for over 20 years. Prior to joining Novartis in 1999, Selzer gained his PhD in computational chemistry from the University of Erlangen-Nuremberg (Erlangen, Germany) before working as a postdoctoral researcher. Selzer has authored a number of high-impact publications in the field and in this interview with Future Medicinal Chemistry, discusses some of the pressing issues in the computational medicinal chemistry arena, current work being conducted by the research group at Novartis, and more. Interview conducted by James Potticary, Assistant Commissioning Editor.
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http://dx.doi.org/10.4155/fmc.14.11DOI Listing
March 2014

Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB.

PLoS One 2013 16;8(10):e77460. Epub 2013 Oct 16.

Molecular Discovery Sciences, MSD Animal Health Innovation GmbH, Schwabenheim, Germany.

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797739PMC
August 2014

Benchmarking of multivariate similarity measures for high-content screening fingerprints in phenotypic drug discovery.

J Biomol Screen 2013 Dec 17;18(10):1284-97. Epub 2013 Sep 17.

1Novartis Institutes for Biomedical Research, Center for Proteomic Chemistry, Basel, Switzerland.

High-content screening (HCS) is a powerful tool for drug discovery being capable of measuring cellular responses to chemical disturbance in a high-throughput manner. HCS provides an image-based readout of cellular phenotypes, including features such as shape, intensity, or texture in a highly multiplexed and quantitative manner. The corresponding feature vectors can be used to characterize phenotypes and are thus defined as HCS fingerprints. Systematic analyses of HCS fingerprints allow for objective computational comparisons of cellular responses. Such comparisons therefore facilitate the detection of different compounds with different phenotypic outcomes from high-throughput HCS campaigns. Feature selection methods and similarity measures, as a basis for phenotype identification and clustering, are critical for the quality of such computational analyses. We systematically evaluated 16 different similarity measures in combination with linear and nonlinear feature selection methods for their potential to capture biologically relevant image features. Nonlinear correlation-based similarity measures such as Kendall's τ and Spearman's ρ perform well in most evaluation scenarios, outperforming other frequently used metrics (such as the Euclidian distance). We also present four novel modifications of the connectivity map similarity that surpass the original version, in our experiments. This study provides a basis for generic phenotypic analysis in future HCS campaigns.
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http://dx.doi.org/10.1177/1087057113501390DOI Listing
December 2013

Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints.

J Med Chem 2013 Jun 13;56(12):4849-59. Epub 2013 Jun 13.

MSD Animal Health Innovation GmbH, Schwabenheim, Germany.

A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR-Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated.
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http://dx.doi.org/10.1021/jm3015734DOI Listing
June 2013

Biodiversity of small molecules--a new perspective in screening set selection.

Drug Discov Today 2013 Jul 20;18(13-14):674-80. Epub 2013 Feb 20.

Cheminformatics and Statistics, Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland.

How is the 'diversity' of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound-target diversity. Biodiverse compound subsets outperform chemically diverse libraries regarding hit rate and the total number of unique chemical scaffolds present among hits. Specifically, by screening ~19% of a HTS collection, we expect to discover ~50-80% of all desired bioactive compounds.
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http://dx.doi.org/10.1016/j.drudis.2013.02.005DOI Listing
July 2013

Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.

PLoS One 2013 25;8(2):e56788. Epub 2013 Feb 25.

MSD Animal Health Innovation GmbH, Schwabenheim, Germany.

The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg(2+) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N(1)-glutathionylation of N(8)-glutathionylspermidine, classifying N(8)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N(8)-glutathionylspermidine was characterised as druggable.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581523PMC
September 2013

Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach.

J Med Chem 2013 Feb 12;56(4):1478-90. Epub 2013 Feb 12.

MSD Animal Health Innovation GmbH, Zur Propstei, D-55270 Schwabenheim, Germany.

In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N-phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy.
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http://dx.doi.org/10.1021/jm3013932DOI Listing
February 2013

High-throughput screening with the Eimeria tenella CDC2-related kinase2/cyclin complex EtCRK2/EtCYC3a.

Microbiology (Reading) 2012 Sep 21;158(Pt 9):2262-2271. Epub 2012 Jun 21.

Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.

The poultry disease coccidiosis, caused by infection with Eimeria spp. apicomplexan parasites, is responsible for enormous economic losses to the global poultry industry. The rapid increase of resistance to therapeutic agents, as well as the expense of vaccination with live attenuated vaccines, requires the development of new effective treatments for coccidiosis. Because of their key regulatory function in the eukaryotic cell cycle, cyclin-dependent kinases (CDKs) are prominent drug targets. The Eimeria tenella CDC2-related kinase 2 (EtCRK2) is a validated drug target that can be activated in vitro by the CDK activator XlRINGO (Xenopus laevis rapid inducer of G2/M progression in oocytes). Bioinformatics analyses revealed four putative E. tenella cyclins (EtCYCs) that are closely related to cyclins found in the human apicomplexan parasite Plasmodium falciparum. EtCYC3a was cloned, expressed in Escherichia coli and purified in a complex with EtCRK2. Using the non-radioactive time-resolved fluorescence energy transfer (TR-FRET) assay, we demonstrated the ability of EtCYC3a to activate EtCRK2 as shown previously for XlRINGO. The EtCRK2/EtCYC3a complex was used for a combined in vitro and in silico high-throughput screening approach, which resulted in three lead structures, a naphthoquinone, an 8-hydroxyquinoline and a 2-pyrimidinyl-aminopiperidine-propane-2-ol. This constitutes a promising starting point for the subsequent lead optimization phase and the development of novel anticoccidial drugs.
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http://dx.doi.org/10.1099/mic.0.059428-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542813PMC
September 2012

[A resistant organism fight with modern weapons. Biology of mycobacteria and new molecular targets].

Pharm Unserer Zeit 2012 Jan;41(1):19-26

Intervet Innovation GmbH, Zur Propstei, Schwabenheim.

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http://dx.doi.org/10.1002/pauz.201100449DOI Listing
January 2012

Differentiation and visualization of diverse cellular phenotypic responses in primary high-content screening.

J Biomol Screen 2012 Jul 6;17(6):843-9. Epub 2012 Mar 6.

Modeling and Simulation, Novartis Campus, Basel, Switzerland.

High-throughput screening, based on subcellular imaging, has become a powerful tool in lead discovery. Through the generation of high-quality images, not only the specific target signal can be analyzed but also phenotypic changes of the whole cell are recorded. Yet analysis strategies for the exploration of high-content screening results, in a manner that is independent from predefined control phenotypes, are largely missing. The approach presented here is based on a well-established modeling technique, self-organizing maps (SOMs), which uses multiparametric results to group treatments that create similar morphological effects. This report describes a novel visualization of the SOM clustering by using an image of the cells from each node, with the most representative cell highlighted to deploy the phenotype described by each node. The approach has the potential to identify both expected hits and novel cellular phenotypes. Moreover, different chemotypes, which cause the same phenotypic effects, are identified, thus facilitating "scaffold hopping."
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http://dx.doi.org/10.1177/1087057112439324DOI Listing
July 2012

Identification of lead compounds targeting the cathepsin B-like enzyme of Eimeria tenella.

Antimicrob Agents Chemother 2012 Mar 5;56(3):1190-201. Epub 2011 Dec 5.

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow, Scotland, United Kingdom.

Cysteine peptidases have been implicated in the development and pathogenesis of Eimeria. We have identified a single-copy cathepsin B-like cysteine peptidase gene in the genome database of Eimeria tenella (EtCatB). Molecular modeling of the predicted protein suggested that it differs significantly from host enzymes and could be a good drug target. EtCatB was expressed and secreted as a soluble, active, glycosylated mature enzyme from Pichia pastoris. Biochemical characterization of the recombinant enzyme confirmed that it is cathepsin B-like. Screening of a focused library against the enzyme identified three inhibitors (a nitrile, a thiosemicarbazone, and an oxazolone) that can be used as leads for novel drug discovery against Eimeria. The oxazolone scaffold is a novel cysteine peptidase inhibitor; it may thus find widespread use.
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http://dx.doi.org/10.1128/AAC.05528-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294901PMC
March 2012

Drug discovery and the use of computational approaches for infectious diseases.

Future Med Chem 2011 Jun;3(8):1011-25

Intervet Innovation GmbH, BioChemInformatics, Zur Propstei, 55270 Schwabenheim, Germany.

For centuries infectious diseases were the scourge of humanity, overcome only by the discovery of vaccination and penicillin. With an armamentarium of effective antibiotics, vaccines and drugs at hand, infectious diseases for many years were considered to be negligible. With the onset of the AIDS pandemic, the return of tuberculosis and influenza (e.g., swine influenza) this notion has changed in recent years. Drug discovery for infectious diseases, therefore, is again gaining increasing interest. This article discusses the drug-discovery process in this area and introduces major computational approaches used to identify suitable drug targets and to discover and optimize chemical lead compounds towards drug candidates using examples from antiparasitic drug discovery.
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http://dx.doi.org/10.4155/fmc.11.60DOI Listing
June 2011

Comparison of multivariate data analysis strategies for high-content screening.

J Biomol Screen 2011 Mar 18;16(3):338-47. Epub 2011 Feb 18.

Novartis Institutes of BioMedical Research, Basel, Switzerland.

High-content screening (HCS) is increasingly used in biomedical research generating multivariate, single-cell data sets. Before scoring a treatment, the complex data sets are processed (e.g., normalized, reduced to a lower dimensionality) to help extract valuable information. However, there has been no published comparison of the performance of these methods. This study comparatively evaluates unbiased approaches to reduce dimensionality as well as to summarize cell populations. To evaluate these different data-processing strategies, the prediction accuracies and the Z' factors of control compounds of a HCS cell cycle data set were monitored. As expected, dimension reduction led to a lower degree of discrimination between control samples. A high degree of classification accuracy was achieved when the cell population was summarized on well level using percentile values. As a conclusion, the generic data analysis pipeline described here enables a systematic review of alternative strategies to analyze multiparametric results from biological systems.
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http://dx.doi.org/10.1177/1087057110395390DOI Listing
March 2011

Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.

ChemMedChem 2010 Aug;5(8):1259-71

Intervet Innovation GmbH, Drug Discovery, Zur Propstei, Schwabenheim, Germany.

Apicomplexan parasites encompass several human- and animal-pathogenic protozoans such as Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin-dependent kinases (CDKs) are key molecules in cell-cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK-like proteins, of which one-E. tenella CDK-related kinase 2 (EtCRK2)-has already been characterized by gene cloning and expression.1 By using the CDK-specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK-like proteins as potential drug targets. An X-ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP-competitive inhibitors. Virtual screening and "wet-bench" high-throughput screening campaigns on large compound libraries resulted in an initial set of hit compounds. These compounds were further analyzed and characterized, leading to a set of four promising lead compounds for development as EtCRK2 inhibitors.
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http://dx.doi.org/10.1002/cmdc.201000157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252702PMC
August 2010

Molecular visualization in the rational drug design process.

Front Biosci (Landmark Ed) 2009 Jan 1;14:2559-83. Epub 2009 Jan 1.

Tripos International, 1699 South Hanley Road, St. Louis, MO 63144-2319, USA.

The visualization of molecular scenarios on an atomic level can help to interpret experimental and theoretical findings. This is demonstrated in this review article with the specific field of drug design. State-of-the-art visualization techniques are described and applied to the different stages of the rational design process. Numerous examples from the literature, in which visualization was used as a major tool in the data analysis and interpretation, are provided to show that images are not only useful for drawing the attention of the reader to a specific paper in a scientific journal.
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http://dx.doi.org/10.2741/3398DOI Listing
January 2009

A comparative chemogenomics strategy to predict potential drug targets in the metazoan pathogen, Schistosoma mansoni.

PLoS One 2009 9;4(2):e4413. Epub 2009 Feb 9.

Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, California, United States of America.

Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for 'druggable' protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635471PMC
April 2009

Estimation of pKa for druglike compounds using semiempirical and information-based descriptors.

J Chem Inf Model 2007 Mar-Apr;47(2):450-9

Novartis Institutes for BioMedical Research, Basel, Switzerland.

A pragmatic approach has been developed for the estimation of aqueous ionization constants (pKa) for druglike compounds. The method involves an algorithm that assigns ionization constants in a stepwise manner to the acidic and basic groups present in a compound. Predictions are made for each ionizable group using models derived from semiempirical quantum chemical properties and information-based descriptors. Semiempirical properties include the partial charge and electrophilic superdelocalizabilty of the atom(s) undergoing protonation or deprotonation. Importantly, the latter property has been extended to allow predictions to be made for multiprotic compounds, overcoming limitations of a previous approach described by Tehan et al. The information-based descriptions include molecular-tree structured fingerprints, based on the methodology outlined by Xing et al., with the addition of 2D substructure flags indicating the presence of other important structural features. These two classes of descriptor were found to complement one another particularly well, resulting in predictive models for a range of functional groups (including alcohols, amidines, amines, anilines, carboxylic acids, guanidines, imidazoles, imines, phenols, pyridines, and pyrimidines). A combined RMSE of 0.48 and 0.81 was obtained for the training set and an external test set compounds, respectively. The predictive models were based on compounds selected from the commercially available BioLoom database. The resultant speed and accuracy of the approach has also enabled the development of Web application on the Novartis intranet for pKa prediction.
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http://dx.doi.org/10.1021/ci600285nDOI Listing
May 2007

Clustering and rule-based classifications of chemical structures evaluated in the biological activity space.

J Chem Inf Model 2007 Mar-Apr;47(2):325-36. Epub 2007 Feb 8.

Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.

Classification methods for data sets of molecules according to their chemical structure were evaluated for their biological relevance, including rule-based, scaffold-oriented classification methods and clustering based on molecular descriptors. Three data sets resulting from uniformly determined in vitro biological profiling experiments were classified according to their chemical structures, and the results were compared in a Pareto analysis with the number of classes and their average spread in the profile space as two concurrent objectives which were to be minimized. It has been found that no classification method is overall superior to all other studied methods, but there is a general trend that rule-based, scaffold-oriented methods are the better choice if classes with homogeneous biological activity are required, but a large number of clusters can be tolerated. On the other hand, clustering based on chemical fingerprints is superior if fewer and larger classes are required, and some loss of homogeneity in biological activity can be accepted.
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http://dx.doi.org/10.1021/ci6004004DOI Listing
May 2007

The response of Mannheimia haemolytica to iron limitation: implications for the acquisition of iron in the bovine lung.

Vet Microbiol 2007 Apr 22;121(3-4):316-29. Epub 2006 Dec 22.

Intervet Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany.

Mannheimia haemolytica is the major causative agent of shipping fever, a severe pneumonia in cattle causing high morbidity and mortality. A prerequisite of successful lung colonization by M. haemolytica is the necessity to adapt to the paucity of iron. The lack of genome information has precluded an assessment of the genetic repertoire available to M. haemolytica to adapt to low iron environments. To close this knowledge-gap, we have determined 90% of a virulent M. haemolytica serotype A1 genome sequence and produced a microarray in order to study gene expression under iron-limiting growth for 15, 30 and 60 min. M. haemolytica responded to iron limitation by the up-regulation of transcripts coding for receptors and ABC-type transporters of transferrin, haemoglobin, haem and siderophores. Real time PCR analysis of lung tissue from Mannheimia-infected calves demonstrated the in vivo transcription of two potential haemoglobin receptors, hmbR1 and hmbR2. The relative hmbR1 and hmbR2 transcript levels in the infected lung tissue were comparable to the induced levels observed under iron-limiting growth, demonstrating in vivo induction of receptor transcription in the context of an infection. When the iron response of M. haemolytica was compared to the iron response of Pasteurella multocida, another pathogen colonizing the bovine lung, only few homologous genes were induced in both organisms. These included the haemoglobin receptor hmbR2 and the periplasmic transport systems yfeABCD and fbpABC. The comparative analysis suggests that the two pathogens use different strategies to adapt to the iron-limiting environment in the bovine host.
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http://dx.doi.org/10.1016/j.vetmic.2006.12.013DOI Listing
April 2007

The impact of tautomer forms on pharmacophore-based virtual screening.

J Chem Inf Model 2006 Nov-Dec;46(6):2342-54

Intervet Innovation GmbH, BioChemInformatics, Zur Propstei, D-55270 Schwabenheim, Germany.

In the field of in silico screening, many applications do not automatically consider possible tautomeric states of molecules. However, the detection of new compound candidates might rely on correct structural description, which is important for the perfect fit toward the biologically relevant interactions. In this paper, we present a new exhaustive tautomer enumeration approach implemented by means of the CACTVS software package. The approach contains a set of 21 predefined SMIRKS-based transforms and a powerful transformation engine that is capable of generating most tautomers described comprehensively in the literature or found in databases in the field of medicinal chemistry. User-defined tautomer rules applied to specific structural databases or scientific issues can be implemented easily and used instead of the predefined rules. In addition, we describe the impact of tautomer-enriched databases on pharmacophore screening approaches for human matrix metalloproteinase 8 as an example of a protein-based pharmacophore screening scenario and for human cyclin-dependent kinases as an example of a ligand-based pharmacophore screening approach. In both test cases, as a preprocessing step, we have used our new tautomer enumerator tool for the tautomer enrichment of the screening data sets and have used it as a postprocessing step to remove tautomeric duplicates from the results. We could demonstrate that the tautomer-enriched screening data sets show significant advantages compared to their non-enhanced counterparts. The discrimination between hits and nonhits was significantly better in the case of tautomer-enriched databases. Moreover, it has been proved that tautomer-enhanced databases will lead to a higher number of potential hits.
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http://dx.doi.org/10.1021/ci060109bDOI Listing
February 2007