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In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation.

Martinčič R, Mravljak J, Švajger U, Perdih A, Anderluh M, Novič M - PLoS ONE (2015)

Bottom Line: A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties.Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives.The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemometrics, National Institute of Chemistry Slovenia, Hajdrihova 19, 1000, Ljubljana, Slovenia.

ABSTRACT
A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties. A final prioritization list of 21 novel compounds alongside 8 established antioxidant compounds was created for their experimental evaluation, consisting of the DPPH assay, 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. Ten novel compounds from the tetronic acid and barbituric acid chemical classes displayed promising antioxidant activity in at least one of the used assays, that is comparable to or even better than some standard antioxidants. Compounds 5, 7 and 9 displayed good activity in all the assays, and were furthermore effective preventers of oxidative stress in human peripheral blood mononuclear cells, which are promising features for the potential therapeutic use of such compounds.

No MeSH data available.


Structures of the novel compounds (1–21) and standard antioxidants, purchased for experimental testing.a Compounds selected by the substructure search; b Compounds selected by pharmacophore screening.
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pone.0140602.g004: Structures of the novel compounds (1–21) and standard antioxidants, purchased for experimental testing.a Compounds selected by the substructure search; b Compounds selected by pharmacophore screening.

Mentions: Next, a few external models provided in the software BIOVIA Pipeline Pilot® version 9.2 (San Diego, CA) were applied to the proposed compounds for the prediction of their aqueous solubility, hepatotoxicity, plasma protein binding, metabolic enzyme CYP2D6 binding, mutagenicity, and ability to cross the blood–brain barrier. On the basis of all the predictions and by following the general guidelines for drug-likeness, a prioritization list of the most promising compounds for experimental testing was created. 21 novel compounds (Fig 4) were obtained from commercial sources; 12 of these were found by a substructure search, while the remaining 9 were selected by pharmacophore screening; the pharmacophore model enabled us to make a scaffold hop from pulvinic acid derivatives by including derivatives of barbituric acid and 3-hydroxy-1,5-dihydro-pyroll-2-one. 8 standard antioxidants were also purchased for the sake of comparison with the novel compounds and validation of the experimental procedures.


In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation.

Martinčič R, Mravljak J, Švajger U, Perdih A, Anderluh M, Novič M - PLoS ONE (2015)

Structures of the novel compounds (1–21) and standard antioxidants, purchased for experimental testing.a Compounds selected by the substructure search; b Compounds selected by pharmacophore screening.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608598&req=5

pone.0140602.g004: Structures of the novel compounds (1–21) and standard antioxidants, purchased for experimental testing.a Compounds selected by the substructure search; b Compounds selected by pharmacophore screening.
Mentions: Next, a few external models provided in the software BIOVIA Pipeline Pilot® version 9.2 (San Diego, CA) were applied to the proposed compounds for the prediction of their aqueous solubility, hepatotoxicity, plasma protein binding, metabolic enzyme CYP2D6 binding, mutagenicity, and ability to cross the blood–brain barrier. On the basis of all the predictions and by following the general guidelines for drug-likeness, a prioritization list of the most promising compounds for experimental testing was created. 21 novel compounds (Fig 4) were obtained from commercial sources; 12 of these were found by a substructure search, while the remaining 9 were selected by pharmacophore screening; the pharmacophore model enabled us to make a scaffold hop from pulvinic acid derivatives by including derivatives of barbituric acid and 3-hydroxy-1,5-dihydro-pyroll-2-one. 8 standard antioxidants were also purchased for the sake of comparison with the novel compounds and validation of the experimental procedures.

Bottom Line: A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties.Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives.The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemometrics, National Institute of Chemistry Slovenia, Hajdrihova 19, 1000, Ljubljana, Slovenia.

ABSTRACT
A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties. A final prioritization list of 21 novel compounds alongside 8 established antioxidant compounds was created for their experimental evaluation, consisting of the DPPH assay, 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. Ten novel compounds from the tetronic acid and barbituric acid chemical classes displayed promising antioxidant activity in at least one of the used assays, that is comparable to or even better than some standard antioxidants. Compounds 5, 7 and 9 displayed good activity in all the assays, and were furthermore effective preventers of oxidative stress in human peripheral blood mononuclear cells, which are promising features for the potential therapeutic use of such compounds.

No MeSH data available.