Non-competitive inhibitor of nucleoside hydrolase from Leishmania donovani identified by fragment-based drug discovery

Alves, Marina Amaral; Nirma, Charlotte; Moreira, M. M.; Soares, Rosemberg O.; Pascutti, Pedro Geraldo; Noël, François; Costa, Paulo R. R.; Sant’Anna, Carlos Maurício R.; Barreiro, Eliezer J.; Lima, L.M.T.R.; Tinoco, Luzineide W.

doi:10.1039/c6ra15143d

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…The process to obtain the nucleoside hydrolase from L. donovani was previously described . In short, the nucleoside hydrolase gene was expressed in Escherichia coli BL21(DE3) cells.…”

Section: Methodsmentioning

confidence: 99%

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An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

et al. 2020

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Nucleoside hydrolases are a strategic target for the development of drugs to treat leishmaniasis, a neglected disease that affects 700 thousand to one million people annually. The present study aimed to identify Leishmania donovani nucleoside hydrolase (LdNH) inhibitors from the leaves of Ormosia arborea, a tree endemic to Brazilian ecosystems, through a strategy based on 1 H NMR analyses and chemometrics. The aqueous EtOH extract of O. arborea leaves inhibited LdNH activity by 95%. The extract was fractionated in triplicate (13 in each step, making a total of 39 fractions). Partial least squares discriminant analysis (PLS-DA) was used to correlate the 1 H NMR spectra of the fractions with their LdNH inhibitory activity and thus to identify the spectral regions associated with the bioactivity. The strategy aimed at isolating the probable bioactive substances and led to two new A-type proanthocyanidins, linked to a p-coumaroyl unit (1 and 2), which appeared as noncompetitive inhibitors of LdNH (IC 50 : 28.2 ± 3.0 μM and 25.6 ± 4.1 μM, respectively). This study confirms the usefulness of the NMR-based chemometric methods to accelerate the discovery of drugs from natural products.

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“…The process to obtain the nucleoside hydrolase from L. donovani was previously described . In short, the nucleoside hydrolase gene was expressed in Escherichia coli BL21(DE3) cells.…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition and kinetic assays were performed for Ld NH as previously described, with slight modifications. In brief, all experiments were carried out in 96-well plates using the spectrophotometric system previously specified.…”

Section: Methodsmentioning

confidence: 99%

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

et al. 2020

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“…It was found out that hydroxychromenone and tetrahydrocyclohexanecarboxylic acid fragments could bind to the enzyme in a fragment-based analysis on LdNH using saturation transfer difference (STD) NMR spectroscopy [176].…”

Section: Nucleoside Hydrolases (Nh Ec 3221)mentioning

confidence: 99%

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Istanbullu¹,

Bayraktar²

2022

Leishmaniasis - General Aspects of a Stigmatized Disease

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The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

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“…These investigations influenced the concept of “privileged scaffolds”, which means that more biologically active compounds build around some structures than others [4] . Nowadays, the “classical” compendium of such structures, generally based on heteroaromatic cores, is supplemented by fused ones, based on heteroaromatic and/or carbo/heteroaliphatic cycles [5] . One of such examples is 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazines.…”

Section: Introductionmentioning

confidence: 99%

Straightforward Synthesis of Functionalized 4,5,6,7‐Tetrahydro‐pyrazolo[1,5‐a]pyrazines – Important Building Blocks for Medicinal Chemistry

et al. 2022

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A set of building blocks based on the 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine scaffold is synthesized in a multigram scale in a cost‐efficient manner. The possibility of the introduction of different substituents, neutral or functionalized in different positions of pyrazole and/or piperazine rings, is shown. The efficacy of using NH‐pyrazole carbonic acids as a key intermediate of the process is demonstrated. The regioselectivity for direct insertion of the substituent to the 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine core is discussed. The synthetic perspectives for using the functionalized 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine as a bifunctional scaffold is discussed. The utilizing of building blocks obtained for the different region‐ and/or stereoselective synthesis, including sole transformations or modifications of functional groups, is demonstrated. The advantages of the proposed approach are proven compared with the other known methodologies.

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Non-competitive inhibitor of nucleoside hydrolase from Leishmania donovani identified by fragment-based drug discovery

Abstract: New non-competitive inhibitor of nucleoside hidrolase fromL. donovaniidentified by fragment-based drug discovery using STD NMR and molecular docking.

Cited by 9 publications

References 33 publications

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Straightforward Synthesis of Functionalized 4,5,6,7‐Tetrahydro‐pyrazolo[1,5‐a]pyrazines – Important Building Blocks for Medicinal Chemistry

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