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Ulrike Wittig

About Ulrike Wittig:
No description specified

SEEK ID: https://fairdomhub.org/people/599

Location:  Germany

Expertise: Biochemistry, Databases, Data Management, Curation

Tools: SABIO-RK, SEEK

ORCID: https://orcid.org/0000-0002-9077-5664

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Project positions

de.NBI-SysBio (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; Kinetics on the move - Workshop 2016 (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; Example use cases (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; SBEpo - Systems Biology of Erythropoietin (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; FAIRDOM & LiSyM & de.NBI Data Structuring Training (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; FAIRDOM (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; EnzymeML (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; GMDS Project Group "FAIRe Dateninfrastrukturen für die Biomedizinische Informatik" (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; FAIRDOM Community Workers (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; MIX-UP (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; Working Group Nicole Radde (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; CEPLAS – Cluster of Excellence on Plant Sciences (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; COVID-19 Disease Map (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; ERNEST Mapping Group Pilot Study (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; NMTrypI - New Medicines for Trypanosomatidic Infections (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; Standardization of enzyme-catalyzed reaction measurement (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; Standardization of enzyme-catalyzed reaction modelling (Heidelberg Institute for Theoretical Studies (HITS gGmbH)) ; ModeleXchange initiative (Heidelberg Institute for Theoretical Studies (HITS gGmbH))

Related items

COVID-19 Disease Map

Here we share resources and best practices to develop a disease map for COVID-19. The project is progressing as a broad community-driven effort. We aim to establish a knowledge repository on virus-host interaction mechanisms specific to the SARS-CoV-2. The COVID-19 Disease Map is an assembly of molecular interaction diagrams established based on literature evidence.

Programme: Disease Maps

Public web page: http://doi.org/10.17881/covid19-disease-map

Standardization of enzyme-catalyzed reaction modelling
No description specified

Programme: FAIR Biocatalysis

Public web page: Not specified

Standardization of enzyme-catalyzed reaction measurement
No description specified

Programme: FAIR Biocatalysis

Public web page: Not specified

EnzymeML
No description specified

Programme: FAIR Biocatalysis

Public web page: Not specified

FAIRDOM

FAIRDOM will establish a support and service network for European Systems Biology. We will serve projects in standardising, managing and disseminating data and models in a FAIR manner: Findable, Accessible, Interoperable and Reusable.

Programme: FAIRDOM

Public web page: http://fair-dom.org/

Start date: 1st Nov 2014

ModeleXchange initiative
No description specified

Programme: COMBINE (Computational Modeling in Biology Network)

Public web page: Not specified

ERNEST Mapping Group Pilot Study
No description specified

Programme: ERNEST - European Research Network on Signal Transduction

Public web page: Not specified

Working Group Nicole Radde

The group around Nicole Radde specializes in the modeling, analysis, and simulation of biochemical systems. This especially includes parameter optimization and identification.

Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: https://www.ist.uni-stuttgart.de/research/group-of-nicole-radde/

Start date: 11th Feb 2020

NMTrypI - New Medicines for Trypanosomatidic Infections

The New Medicines for Trypanosomatidic Infections - NMTrypI project aimed at obtaining new candidate drugs against Trypanosomatidic infections with appropriate efficiency from the lead phase to the final preclinical phase that are more accessible to patients.

Programme: Drug development for neglected parasitic diseases

Public web page: https://fp7-nmtrypi.eu/

Start date: 1st Feb 2014

End date: 31st Jan 2017

SBEpo - Systems Biology of Erythropoietin

Multi-level mathematical modeling of erythropoiesis for optimized expansion of erythroid progenitor cells and improved treatment regimes

Programme: e:Bio

Public web page: Not specified

MIX-UP
No description specified

Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: Not specified

CEPLAS – Cluster of Excellence on Plant Sciences

SMART Plants for Tomorrow’s Needs

Plants enable life on Earth through the conversion of solar energy into chemical energy. Beginning with the Neolithic Revolution, the domestication of plants provided the basis for human population growth and, subsequently, the evolution of highly developed civilizations. However, the growing food demands imposed by an increasing population and the effects of anthropogenic climate change pose huge challenges for sustainable food production and ecosystem maintenance.
...

Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: https://www.ceplas.eu/en/home/

FAIRDOM Community Workers

Collection of training material for SEEK/FAIRDOMHub

Programme: FAIRDOM

Public web page: Not specified

GMDS Project Group "FAIRe Dateninfrastrukturen für die Biomedizinische Informatik"

The GMDS project group bundles activities for health-related FAIR data infrastructures in the fields of biomedical research, clinical data management and medical informatics in Germany. It aims at providing a platform for information exchange about best practice for and implementation of FAIR data management in these fields and constructing a network of FAIR data managements providers in these fields. Through bridging between providers and potential users of such data management platforms within
...

Programme: German Association for Medical Informatics, Biometry and Epidemiology (GMDS)

Public web page: https://gmds.de/aktivitaeten/medizinische-informatik/projektgruppenseiten/faire-dateninfrastrukturen-fuer-die-biomedizinische-informatik/

Start date: 28th Feb 2019

End date: 27th Feb 2022

de.NBI-SysBio

The Systems Biology Service Center of de.NBI (de.NBI-SysBio) provides bioinformatics support and a standards-based data management for systems biology projects, with focus on the provenance of experimental results and on the reproducibility of modeling experiments, as well as high-quality curated biochemical data to modelers and experimentalists.
The node concentrates on two tools for the data management in life sciences research: SEEK, a catalogue for storage, registration and exchange of data
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Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: Not specified

FAIRDOM & LiSyM & de.NBI Data Structuring Training
No description specified

Programme: LiSyM - Systems Medicine of the Liver

Public web page: https://www.fairdomhub.org/events/96

Example use cases

Public showcase and collection of training material

Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: http://www.denbi.de

Kinetics on the move - Workshop 2016

The workshop focuses on the publication, curation, retrieval, and usage of kinetic data from the reaction kinetics database SABIO-RK and on the use of data in modeling. There will be experience reports from scientists who successfully used experimental data to formulate or verify biological hypotheses with the computer, and you will experience how experimental data can be used with computational models.

Programme: de.NBI Systems Biology Service Center (de.NBI-SysBio)

Public web page: http://www.h-its.org/event/kinetics-on-the-move/

Data Management and Data Standardization
SBEpo - Systems Biology of Erythropoietin
No description specified

Snapshots: No snapshots

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SABIO-RK hands-on training results 2019
de.NBI-SysBio
No description specified

Creator: Ulrike Wittig

Submitter: Maja Rey

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SEEK tasks for hands on training
de.NBI-SysBio
No description specified

Creators: Maja Rey, Ulrike Wittig

Submitter: Maja Rey

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SABIO-RK results for hands on training
de.NBI-SysBio
No description specified

Creators: Maja Rey, Ulrike Wittig

Submitter: Maja Rey

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SABIO-RK tasks for hands on training
de.NBI-SysBio
No description specified

Creators: Ulrike Wittig, Maja Rey

Submitter: Maja Rey

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Workshop agenda
Kinetics on the move - Workshop 2016
No description specified

Creator: Ulrike Wittig

Submitter: Ulrike Wittig

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SABIO-RK documentation user interface
Kinetics on the move - Workshop 2016
No description specified

Creator: Ulrike Wittig

Submitter: Ulrike Wittig

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SABIO-RK documentation web services
Kinetics on the move - Workshop 2016
No description specified

Creator: Ulrike Wittig

Submitter: Ulrike Wittig

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The first 10 years of the international coordination network for standards in systems and synthetic biology (COMBINE)
FAIRDOM, LiSyM Core Infrastructure and Management (LiSyM-PD), COMBINE Multicellular Modelling, GMDS Project Group "FAIRe Dateninfrastrukturen für die Biomedizinische Informatik", COVID-19 Disease Map

Abstract (Expand)

This paper presents a report on outcomes of the 10th Computational Modeling in Biology Network (COMBINE) meeting that was held in Heidelberg, Germany, in July of 2019. The annual event brings together … researchers, biocurators and software engineers to present recent results and discuss future work in the area of standards for systems and synthetic biology. The COMBINE initiative coordinates the development of various community standards and formats for computational models in the life sciences. Over the past 10 years, COMBINE has brought together standard communities that have further developed and harmonized their standards for better interoperability of models and data. COMBINE 2019 was co-located with a stakeholder workshop of the European EU-STANDS4PM initiative that aims at harmonized data and model standardization for in silico models in the field of personalized medicine, as well as with the FAIRDOM PALs meeting to discuss findable, accessible, interoperable and reusable (FAIR) data sharing. This report briefly describes the work discussed in invited and contributed talks as well as during breakout sessions. It also highlights recent advancements in data, model, and annotation standardization efforts. Finally, this report concludes with some challenges and opportunities that this community will face during the next 10 years.

Authors: Dagmar Waltemath, Martin Golebiewski, Michael L Blinov, Padraig Gleeson, Henning Hermjakob, Michael Hucka, Esther Thea Inau, Sarah M Keating, Matthias König, Olga Krebs, Rahuman S Malik-Sheriff, David Nickerson, Ernst Oberortner, Herbert M Sauro, Falk Schreiber, Lucian Smith, Melanie I Stefan, Ulrike Wittig, Chris J Myers

Date Published: 29th Jun 2020

Publication Type: Journal

Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different … medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.

Authors: P. Linciano, G. Cullia, C. Borsari, M. Santucci, S. Ferrari, G. Witt, S. Gul, M. Kuzikov, B. Ellinger, N. Santarem, A. Cordeiro da Silva, P. Conti, M. L. Bolognesi, M. Roberti, F. Prati, F. Bartoccini, M. Retini, G. Piersanti, A. Cavalli, L. Goldoni, S. M. Bertozzi, F. Bertozzi, E. Brambilla, V. Rizzo, D. Piomelli, A. Pinto, T. Bandiera, M. P. Costi

Date Published: 1st Mar 2020

Publication Type: Journal

Data Management in Computational Systems Biology: Exploring Standards, Tools, Databases, and Packaging Best Practices.
FAIRDOM, LiSyM Core Infrastructure and Management (LiSyM-PD), COMBINE Multicellular Modelling, COVID-19 Disease Map

Abstract (Expand)

Computational systems biology involves integrating heterogeneous datasets in order to generate models. These models can assist with understanding and prediction of biological phenomena. Generating … datasets and integrating them into models involves a wide range of scientific expertise. As a result these datasets are often collected by one set of researchers, and exchanged with others researchers for constructing the models. For this process to run smoothly the data and models must be FAIR-findable, accessible, interoperable, and reusable. In order for data and models to be FAIR they must be structured in consistent and predictable ways, and described sufficiently for other researchers to understand them. Furthermore, these data and models must be shared with other researchers, with appropriately controlled sharing permissions, before and after publication. In this chapter we explore the different data and model standards that assist with structuring, describing, and sharing. We also highlight the popular standards and sharing databases within computational systems biology.

Authors: N. J. Stanford, M. Scharm, P. D. Dobson, M. Golebiewski, M. Hucka, V. B. Kothamachu, D. Nickerson, S. Owen, J. Pahle, U. Wittig, D. Waltemath, C. Goble, P. Mendes, J. Snoep

Date Published: 12th Oct 2019

Publication Type: Journal

Excited-state intramolecular proton transfer in a bioactive flavonoid provides fluorescence observables for recognizing its engagement with target proteins.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

A benzothiophene-substituted chromenone with promising activity against Leishmania and Trypanosoma species exhibits peculiar fluorescence properties useful for identifying its complexes with target … proteins in the microorganism proteomes. The emission spectra, anisotropy and time profiles of this flavonoid strongly change when moving from the free to the protein-bound forms. The same two types of emission are observed in organic solvents and their mixtures with water, with the relative band intensities depending on the solvent ability to establish hydrogen bonds with the solute. The regular emission prevails in protic solvents, while in aprotic solvents the anomalously red-shifted emission occurs from a zwitterionic tautomeric form, produced in the excited state by proton transfer within the intramolecularly H-bonded form. This interpretation finds support from an experimental and theoretical investigation of the conformational preferences of this compound in the ground and lowest excited state, with a focus on the relative twisting about the chromenone-benzothiophene interconnecting bond. An analysis of the absorption and emission spectra and of the photophysical properties of the two emitting tautomers highlights the relevance of the local microenvironment, particularly of the intra- and intermolecular hydrogen bonds in which this bioactive compound is involved, in determining both its steady-state and time-resolved fluorescence behaviour.

Authors: D. Vanossi, M. Caselli, G. Pavesi, C. Borsari, P. Linciano, M. P. Costi, G. Ponterini

Date Published: 1st Sep 2019

Publication Type: Journal

Medicinal Chemistry of Neglected and Tropical Diseases
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract

Not specified

Authors: Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay

Date Published: 15th Aug 2019

Publication Type: Book

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid … parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

Authors: G. Landi, P. Linciano, C. Borsari, C. P. Bertolacini, C. B. Moraes, A. Cordeiro-da-Silva, S. Gul, G. Witt, M. Kuzikov, M. P. Costi, C. Pozzi, S. Mangani

Date Published: 12th Jul 2019

Publication Type: Journal

Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography … guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC50 = 0.35 muM; LmPTR1 IC50 = 1.9 muM) and low muM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 muM). Formulation of 4c with hydroxypropyl-beta-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.

Authors: P. Linciano, C. Pozzi, L. D. Iacono, F. di Pisa, G. Landi, A. Bonucci, S. Gul, M. Kuzikov, B. Ellinger, G. Witt, N. Santarem, C. Baptista, C. Franco, C. B. Moraes, W. Muller, U. Wittig, R. Luciani, A. Sesenna, A. Quotadamo, S. Ferrari, I. Pohner, A. Cordeiro-da-Silva, S. Mangani, L. Costantino, M. P. Costi

Date Published: 25th Apr 2019

Publication Type: Journal

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. … Herein, we have performed structure-activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 muM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

Authors: C. Borsari, N. Santarem, S. Macedo, M. D. Jimenez-Anton, J. J. Torrado, A. I. Olias-Molero, M. J. Corral, A. Tait, S. Ferrari, L. Costantino, R. Luciani, G. Ponterini, S. Gul, M. Kuzikov, B. Ellinger, B. Behrens, J. Reinshagen, J. M. Alunda, A. Cordeiro-da-Silva, M. P. Costi

Date Published: 11th Apr 2019

Publication Type: Journal

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes … sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

Authors: C. B. Moraes, G. Witt, M. Kuzikov, B. Ellinger, T. Calogeropoulou, K. C. Prousis, S. Mangani, F. Di Pisa, G. Landi, L. D. Iacono, C. Pozzi, L. H. Freitas-Junior, B. Dos Santos Pascoalino, C. P. Bertolacini, B. Behrens, O. Keminer, J. Leu, M. Wolf, J. Reinshagen, A. Cordeiro-da-Silva, N. Santarem, A. Venturelli, S. Wrigley, D. Karunakaran, B. Kebede, I. Pohner, W. Muller, J. Panecka-Hofman, R. C. Wade, M. Fenske, J. Clos, J. M. Alunda, M. J. Corral, E. Uliassi, M. L. Bolognesi, P. Linciano, A. Quotadamo, S. Ferrari, M. Santucci, C. Borsari, M. P. Costi, S. Gul

Date Published: 21st Feb 2019

Publication Type: Journal

Pharmacokinetics and disposition of miltefosine in healthy mice and hamsters experimentally infected with Leishmania infantum.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Miltefosine is the only currently available oral drug for treatment of leishmaniasis. However, information on the pharmacokinetics (PK) of miltefosine is relatively scarce in animals. PK parameters and … disposition of the molecule was determined in healthy NMRI mice and Syrian hamsters infected and treated with different miltefosine doses and regimens. Long half-life of the molecule was confirmed and differential pattern of accumulation of the drug was observed in analyzed organs in mice and hamster. Long treatment schedules produced miltefosine levels over IC50 value against L. infantum intracellular amastigotes for at least 24days in spleen and liver of infected hamsters. The observed differential pattern of organ accumulation of the drug in mice and hamster supports the relevance of both species for translational research on chemotherapy of leishmaniasis.

Authors: M. D. Jimenez-Anton, E. Garcia-Calvo, C. Gutierrez, M. D. Escribano, N. Kayali, J. L. Luque-Garcia, A. I. Olias-Molero, M. J. Corral, M. P. Costi, J. J. Torrado, J. M. Alunda

Date Published: 30th Aug 2018

Publication Type: Journal

Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy … of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phen othiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-ph enothiazine (12) showed respective IC50 values of 1.8 and 1.9 mug mL(-1) against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.

Authors: E. Uliassi, L. Piazzi, F. Belluti, A. Mazzanti, M. Kaiser, R. Brun, C. B. Moraes, L. H. Freitas-Junior, S. Gul, M. Kuzikov, B. Ellinger, C. Borsari, M. P. Costi, M. L. Bolognesi

Date Published: 6th Apr 2018

Publication Type: Journal

Aryl thiosemicarbazones for the treatment of trypanosomatidic infections.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Basing on a library of thiadiazole derivatives showing anti-trypanosomatidic activity, we have considered the thiadiazoles opened forms and reaction intermediates, thiosemicarbazones, as compounds of … interest for phenotypic screening against Trypanosoma brucei (Tb), intracellular amastigote form of Leishmania infantum (Li) and Trypanosoma cruzi (Tc). Similar compounds have already shown interesting activity against the same organisms. The compounds were particularly effective against T. brucei and T. cruzi. Among the 28 synthesized compounds, the best one was (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene) hydrazinecarbothioamide (A14) yielding a comparable anti-parasitic activity against the three parasitic species (TbEC50=2.31muM, LiEC50=6.14muM, TcEC50=1.31muM) and a Selectivity Index higher than 10 with respect to human macrophages, therefore showing a pan-anti-trypanosomatidic activity. (E)-2-((3'.4'-dimethoxy-[1.1'-biphenyl]-3-yl)methyle ne) hydrazinecarbothioamide (A12) and (E)-2-(4-((3.4-dichlorobenzyl)oxy)benzylidene)hydrazine carbothioamide (A14) were able to potentiate the anti-parasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, yielding a 6-fold and 4-fold respectively Dose Reduction Index for MTX. The toxicity profile against four human cell lines and a panel of in vitro early-toxicity assays (comprising hERG, Aurora B, five cytochrome P450 isoforms and mitochondrial toxicity) demonstrated the low toxicity for the thosemicarbazones class in comparison with known drugs. The results confirmed thiosemicarbazones as a suitable chemical scaffold with potential for the development of properly decorated new anti-parasitic drugs.

Authors: P. Linciano, C. B. Moraes, L. M. Alcantara, C. H. Franco, B. Pascoalino, L. H. Freitas-Junior, S. Macedo, N. Santarem, A. Cordeiro-da-Silva, S. Gul, G. Witt, M. Kuzikov, B. Ellinger, S. Ferrari, R. Luciani, A. Quotadamo, L. Costantino, M. P. Costi

Date Published: 25th Feb 2018

Publication Type: Journal

SABIO-RK: an updated resource for manually curated biochemical reaction kinetics.
de.NBI-SysBio

Abstract (Expand)

SABIO-RK (http://sabiork.h-its.org/) is a manually curated database containing data about biochemical reactions and their reaction kinetics. The data are primarily extracted from scientific literature … and stored in a relational database. The content comprises both naturally occurring and alternatively measured biochemical reactions and is not restricted to any organism class. The data are made available to the public by a web-based search interface and by web services for programmatic access. In this update we describe major improvements and extensions of SABIO-RK since our last publication in the database issue of Nucleic Acid Research (2012). (i) The website has been completely revised and (ii) allows now also free text search for kinetics data. (iii) Additional interlinkages with other databases in our field have been established; this enables users to gain directly comprehensive knowledge about the properties of enzymes and kinetics beyond SABIO-RK. (iv) Vice versa, direct access to SABIO-RK data has been implemented in several systems biology tools and workflows. (v) On request of our experimental users, the data can be exported now additionally in spreadsheet formats. (vi) The newly established SABIO-RK Curation Service allows to respond to specific data requirements.

Authors: U. Wittig, M. Rey, A. Weidemann, R. Kania, W. Muller

Date Published: 4th Jan 2018

Publication Type: Journal

Scaffolds and Biological Targets Avenue to Fight Against Drug Resistance in Leishmaniasis
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract

Not specified

Authors: Chiara Borsari, Antonio Quotadamo, Stefania Ferrari, Alberto Venturelli, Anabela Cordeiro-da-Silva, Nuno Santarem, Maria Paola Costi

Date Published: 2018

Publication Type: InBook

In Silico Identification and In Vitro Evaluation of Natural Inhibitors of Leishmania major Pteridine Reductase I.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

In a continuation of our computational efforts to find new natural inhibitors of a variety of target enzymes from parasites causing neglected tropical diseases (NTDs), we now report on 15 natural … products (NPs) that we have identified as inhibitors of Leishmania major pteridine reductase I (LmPTR1) through a combination of in silico and in vitro investigations. Pteridine reductase (PTR1) is an enzyme of the trypanosomatid parasites' peculiar folate metabolism, and has previously been validated as a drug target. Initially, pharmacophore queries were created based on four 3D structures of LmPTR1 using co-crystallized known inhibitors as templates. Each of the pharmacophore queries was used to virtually screen a database of 1100 commercially available natural products. The resulting hits were submitted to molecular docking analyses in the substrate binding site of the respective protein structures used for the pharmacophore design. This approach led to the in silico identification of a total of 18 NPs with predicted binding affinity to LmPTR1. These compounds were subsequently tested in vitro for inhibitory activity towards recombinant LmPTR1 in a spectrophotometric inhibition assay. Fifteen out of the 18 tested compounds (hit rate = 83%) showed significant inhibitory activity against LmPTR1 when tested at a concentration of 50 microM. The IC50 values were determined for the six NPs that inhibited the target enzyme by more than 50% at 50 microM, with sophoraflavanone G being the most active compound tested (IC50 = 19.2 microM). The NPs identified and evaluated in the present study may represent promising lead structures for the further rational drug design of more potent inhibitors against LmPTR1.

Authors: F. C. Herrmann, N. Sivakumar, J. Jose, M. P. Costi, C. Pozzi, T. J. Schmidt

Date Published: 6th Dec 2017

Publication Type: Journal

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic … core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 muM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 muM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 muM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.

Authors: E. Uliassi, G. Fiorani, R. L. Krauth-Siegel, C. Bergamini, R. Fato, G. Bianchini, J. Carlos Menendez, M. T. Molina, E. Lopez-Montero, F. Falchi, A. Cavalli, S. Gul, M. Kuzikov, B. Ellinger, G. Witt, C. B. Moraes, L. H. Freitas-Junior, C. Borsari, M. P. Costi, M. L. Bolognesi

Date Published: 1st Dec 2017

Publication Type: Journal

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major … PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 muM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

Authors: P. Linciano, A. Dawson, I. Pohner, D. M. Costa, M. S. Sa, A. Cordeiro-da-Silva, R. Luciani, S. Gul, G. Witt, B. Ellinger, M. Kuzikov, P. Gribbon, J. Reinshagen, M. Wolf, B. Behrens, V. Hannaert, P. A. M. Michels, E. Nerini, C. Pozzi, F. di Pisa, G. Landi, N. Santarem, S. Ferrari, P. Saxena, S. Lazzari, G. Cannazza, L. H. Freitas-Junior, C. B. Moraes, B. S. Pascoalino, L. M. Alcantara, C. P. Bertolacini, V. Fontana, U. Wittig, W. Muller, R. C. Wade, W. N. Hunter, S. Mangani, L. Costantino, M. P. Costi

Date Published: 30th Sep 2017

Publication Type: Journal

Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known … human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor beta, a folate/antifolate transporter. METHODS: We computationally compared the structural, dynamic and physico-chemical properties of the targets. We based our analysis on available inhibitory activity and crystallographic data, including a crystal structure of the bifunctional T. cruzi DHFR-TS with tetrahydrofolate bound determined in this work. Due to the low sequence and structural similarity of the targets analyzed, we employed a mapping of binding pockets based on the known common ligands, folate and methotrexate. RESULTS: Our analysis provides a set of practical strategies for the design of selective trypanosomatid folate pathway inhibitors, which are supported by enzyme inhibition measurements and crystallographic structures. CONCLUSIONS: The ligand-based comparative computational mapping of protein binding pockets provides a basis for repurposing of anti-folates and the design of new anti-trypanosmatid agents. GENERAL SIGNIFICANCE: Apart from the target-based discovery of selective compounds, our approach may be also applied for protein engineering or analyzing evolutionary relationships in protein families.

Authors: J. Panecka-Hofman, I. Pohner, F. Spyrakis, T. Zeppelin, F. Di Pisa, L. Dello Iacono, A. Bonucci, A. Quotadamo, A. Venturelli, S. Mangani, M. P. Costi, R. C. Wade

Date Published: 25th Sep 2017

Publication Type: Journal

The Future of Drug Development for Neglected Tropical Diseases: How the European Commission Can Continue to Make a Difference.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

In this article, the four coordinators of neglected tropical disease (NTD) drug development projects funded under the European Commission (EC) Framework Programme 7 argue that the EC should reassess … their funding strategy to cover the steps necessary to translate a lead compound into a drug candidate for testing in clinical trials, and suggest ways in which this might be achieved.

Authors: R. J. Pierce, J. MacDougall, R. Leurs, M. P. Costi

Date Published: 23rd May 2017

Publication Type: Journal

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues … (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Authors: F. Di Pisa, G. Landi, L. Dello Iacono, C. Pozzi, C. Borsari, S. Ferrari, M. Santucci, N. Santarem, A. Cordeiro-da-Silva, C. B. Moraes, L. M. Alcantara, V. Fontana, L. H. Freitas-Junior, S. Gul, M. Kuzikov, B. Behrens, I. Pohner, R. C. Wade, M. P. Costi, S. Mangani

Date Published: 8th Mar 2017

Publication Type: Journal

Introduction to SABIO-RK 2019
de.NBI-SysBio
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Creator: Ulrike Wittig

Submitter: Maja Rey

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SABIO-RK: Finding, curating, and publishing data
Kinetics on the move - Workshop 2016
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Creator: Ulrike Wittig

Submitter: Ulrike Wittig

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