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7 Publications matching the given criteria: (Clear all filters)
Published year: 20197
Data Management in Computational Systems Biology: Exploring Standards, Tools, Databases, and Packaging Best Practices.

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.

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

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.

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.

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.

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.

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

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