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Rebecca Wade

About Rebecca Wade:

Group Leader, Molecular and Cellular Modeling Group, EML Research, Heidelberg

SEEK ID: https://fairdomhub.org/people/55

Location:  Germany

Expertise: computational structural biology, protein interactions, molecular modeling, molecular simulation

Tools: molecular modeling and simulation, PIPSA, SYCAMORE

ORCID: Not specified

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Related items

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

SysMO-LAB

Comparative Systems Biology: Lactic Acid Bacteria

Programme: SysMO

Public web page: http://www.sysmo.net/index.php?index=57

PYK structural models
SysMO-LAB

Structural models of the LAB PYKs of L. lactis, L. plantarum, S. pyogenes and E. faecalis including the "best" docking solutions of potential allosteric ligands. The structures were derived by homology modeling based on the template of E. coli and B. stearothermophilus.
PYK models and ligands are provided as .pdb files and can be displayed by using the program PyMOL, for instance.

Creators: Nadine Veith, Anna Feldman-Salit, Stefan Henrich, Rebecca Wade

Submitter: Nadine Veith

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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

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

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

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.
NMTrypI - New Medicines for Trypanosomatidic Infections

Abstract (Expand)

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic … screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 muM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 muM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

Authors: C. Borsari, R. Luciani, C. Pozzi, I. Poehner, S. Henrich, M. Trande, A. Cordeiro-da-Silva, N. Santarem, C. Baptista, A. Tait, F. Di Pisa, L. Dello Iacono, G. Landi, S. Gul, M. Wolf, M. Kuzikov, B. Ellinger, J. Reinshagen, G. Witt, P. Gribbon, M. Kohler, O. Keminer, B. Behrens, L. Costantino, P. Tejera Nevado, E. Bifeld, J. Eick, J. Clos, J. Torrado, M. D. Jimenez-Anton, M. J. Corral, J. M. Alunda, F. Pellati, R. C. Wade, S. Ferrari, S. Mangani, M. P. Costi

Date Published: 25th Aug 2016

Publication Type: Journal

Organism-Adapted Specificity of the Allosteric Regulation of Pyruvate Kinase in Lactic Acid Bacteria
SysMO-LAB

Abstract

Not specified

Editor:

Date Published: 25th Jul 2013

Publication Type: Not specified

Regulation of the Activity of Lactate Dehydrogenases from Four Lactic Acid Bacteria
SysMO-LAB

Abstract

Not specified

Authors: , , H. Messiha, , , , , , ,

Date Published: 17th May 2013

Publication Type: Not specified

Comparative computational analysis of enzyme allosteric sites and the binding of allosteric effectors.
SysMO-LAB

Poster presented at the 12th International Conference on Systems Biology (ICSB), Heidelberg/Mannheim, August 28 - September 1, 2011.

Creators: Stefan Henrich, Rebecca Wade, Anna Feldman-Salit, Nadine Veith

Submitter: Stefan Henrich

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