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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 ROC curve, obtained from the Plot ROC curve tool in the LigandScout screening module, together with the corresponding output values of AUC and EF.
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pone.0140602.g012: The ROC curve, obtained from the Plot ROC curve tool in the LigandScout screening module, together with the corresponding output values of AUC and EF.

Mentions: The obtained pharmacophore model was successfully validated utilizing the Plot ROC curve tool in the LigandScout screening module, which performs the screening a series of known active and inactive compounds, constructs a receiver operating characteristic (ROC) curve [73,74] and outputs the area under the ROC curve (AUC) and the enrichment factor. The active and inactive pulvinic acid derivatives were selected on the basis of their experimentally determined antioxidant activity in the thymidine protection assay under the influence of different oxidative stressors [6]; the compounds that were on average among the most active in all the oxidative conditions were selected as active, while the compounds that were on average the least active in all the conditions were selected as inactive. The sets of active and inactive compound contained nine molecules each, and the set of actives included also the four compounds that were used for the development of the pharmacophore model; the structures of the compounds used for the pharmacophore model validation are provided in the S2 Table of the Supporting Information. The model successfully identified all 9 active compounds, while 8 of the decoys were determined as inactive and only 1 was misclassified as active. The models ability to discriminate active from inactive compounds is reflected by the AUC value, where the maximal possible value is 1; the AUC value obtained at 100% of the collection of active and inactive compounds had a satisfactory value of 0.94 (Fig 12). Another output parameter was the enrichment factor (EF), which reflects the capability of a screening tool to detect active compounds in comparison to a random selection [75]; the value should be always greater than 1, and our model produced a value of 1.8 at 100% of the collection of active and inactive compounds.


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 ROC curve, obtained from the Plot ROC curve tool in the LigandScout screening module, together with the corresponding output values of AUC and EF.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140602.g012: The ROC curve, obtained from the Plot ROC curve tool in the LigandScout screening module, together with the corresponding output values of AUC and EF.
Mentions: The obtained pharmacophore model was successfully validated utilizing the Plot ROC curve tool in the LigandScout screening module, which performs the screening a series of known active and inactive compounds, constructs a receiver operating characteristic (ROC) curve [73,74] and outputs the area under the ROC curve (AUC) and the enrichment factor. The active and inactive pulvinic acid derivatives were selected on the basis of their experimentally determined antioxidant activity in the thymidine protection assay under the influence of different oxidative stressors [6]; the compounds that were on average among the most active in all the oxidative conditions were selected as active, while the compounds that were on average the least active in all the conditions were selected as inactive. The sets of active and inactive compound contained nine molecules each, and the set of actives included also the four compounds that were used for the development of the pharmacophore model; the structures of the compounds used for the pharmacophore model validation are provided in the S2 Table of the Supporting Information. The model successfully identified all 9 active compounds, while 8 of the decoys were determined as inactive and only 1 was misclassified as active. The models ability to discriminate active from inactive compounds is reflected by the AUC value, where the maximal possible value is 1; the AUC value obtained at 100% of the collection of active and inactive compounds had a satisfactory value of 0.94 (Fig 12). Another output parameter was the enrichment factor (EF), which reflects the capability of a screening tool to detect active compounds in comparison to a random selection [75]; the value should be always greater than 1, and our model produced a value of 1.8 at 100% of the collection of active and inactive compounds.

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.