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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.


The workflow of the presented study, combining in silico and in vitro approaches.
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pone.0140602.g002: The workflow of the presented study, combining in silico and in vitro approaches.

Mentions: In the presented work we utilized the combination of in silico and in vitro approaches directed towards the discovery of novel potent antioxidants on the basis of pulvinic acid and coumarine derivatives. The workflow of our study is depicted in Fig 2. The in silico part began with the virtual screening of commercial compounds libraries, either by utilizing the 2D substructure search or by the use of the ligand-based pharmacophore model derived from our starting antioxidant compounds. Next, the obtained hits were manually refined (a detailed explanation is presented under Results and discussion) and the antioxidant activity of the selected compounds was predicted using the consensus results from our previously developed QSAR models [6]. A couple of pharmacokinetic parameters of the compounds (absorption, solubility) and some toxicity parameters (hepatotoxicity, CYP2D6 inhibition, mutagenicity, carcinogenicity, developmental toxicity) were also evaluated using commercially available models. On the basis of the combined in silico results, a final enriched library of compounds for the experimental screening was created. The initial experimental evaluation was carried out using the DPPH assay and the most promising compounds were subsequently investigated by 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. In every step of the experimental evaluation the activities of novel compounds were compared to the activities of standard antioxidants. We were successful in our aim of discovering novel potent antioxidants, since almost half of the compounds selected in silico displayed in vitro antioxidant activity.


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)

The workflow of the presented study, combining in silico and in vitro approaches.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140602.g002: The workflow of the presented study, combining in silico and in vitro approaches.
Mentions: In the presented work we utilized the combination of in silico and in vitro approaches directed towards the discovery of novel potent antioxidants on the basis of pulvinic acid and coumarine derivatives. The workflow of our study is depicted in Fig 2. The in silico part began with the virtual screening of commercial compounds libraries, either by utilizing the 2D substructure search or by the use of the ligand-based pharmacophore model derived from our starting antioxidant compounds. Next, the obtained hits were manually refined (a detailed explanation is presented under Results and discussion) and the antioxidant activity of the selected compounds was predicted using the consensus results from our previously developed QSAR models [6]. A couple of pharmacokinetic parameters of the compounds (absorption, solubility) and some toxicity parameters (hepatotoxicity, CYP2D6 inhibition, mutagenicity, carcinogenicity, developmental toxicity) were also evaluated using commercially available models. On the basis of the combined in silico results, a final enriched library of compounds for the experimental screening was created. The initial experimental evaluation was carried out using the DPPH assay and the most promising compounds were subsequently investigated by 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. In every step of the experimental evaluation the activities of novel compounds were compared to the activities of standard antioxidants. We were successful in our aim of discovering novel potent antioxidants, since almost half of the compounds selected in silico displayed in vitro antioxidant activity.

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.