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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.


a) The derived pharmacophore model, together with aligned four active pulvinic acid derivatives (IDs: 11, 15, 36, 49 [6]), used in the model development; b) hit compound 13 from the barbituric acid chemical class, aligned to the derived pharmacophore model; this represents a successful scaffold hop from the pulvinic acid scaffold.Yellow sphere–area of hydrophobic interactions; red spheres–hydrogen bond acceptors; green sphere–hydrogen bond donor; blue circle–aromatic ring; grey spheres–exclusion volume spheres.
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pone.0140602.g003: a) The derived pharmacophore model, together with aligned four active pulvinic acid derivatives (IDs: 11, 15, 36, 49 [6]), used in the model development; b) hit compound 13 from the barbituric acid chemical class, aligned to the derived pharmacophore model; this represents a successful scaffold hop from the pulvinic acid scaffold.Yellow sphere–area of hydrophobic interactions; red spheres–hydrogen bond acceptors; green sphere–hydrogen bond donor; blue circle–aromatic ring; grey spheres–exclusion volume spheres.

Mentions: To further enrich the pool with additional compounds that would be structurally diverse from the chemical class of pulvinic acids, a validated ligand-based pharmacophore model was used in the screening of our in house virtual library, consisting of about two million commercially available compounds from the vendors Vitas-M and ChemDiv. The final pharmacophore model derived on the basis of four selected pulvinic acid derivatives was composed of 6 pharmacophore features: a hydrogen bond donor, three hydrogen bond acceptors, aromatic ring and an area of hydrophobic interactions. The features were surrounded by exclusion volume spheres to limit the space available for the investigated molecules (Fig 3). More details on the development of the pharmacophore model and its application in the virtual screening are provided in section 4.1.3.


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)

a) The derived pharmacophore model, together with aligned four active pulvinic acid derivatives (IDs: 11, 15, 36, 49 [6]), used in the model development; b) hit compound 13 from the barbituric acid chemical class, aligned to the derived pharmacophore model; this represents a successful scaffold hop from the pulvinic acid scaffold.Yellow sphere–area of hydrophobic interactions; red spheres–hydrogen bond acceptors; green sphere–hydrogen bond donor; blue circle–aromatic ring; grey spheres–exclusion volume spheres.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140602.g003: a) The derived pharmacophore model, together with aligned four active pulvinic acid derivatives (IDs: 11, 15, 36, 49 [6]), used in the model development; b) hit compound 13 from the barbituric acid chemical class, aligned to the derived pharmacophore model; this represents a successful scaffold hop from the pulvinic acid scaffold.Yellow sphere–area of hydrophobic interactions; red spheres–hydrogen bond acceptors; green sphere–hydrogen bond donor; blue circle–aromatic ring; grey spheres–exclusion volume spheres.
Mentions: To further enrich the pool with additional compounds that would be structurally diverse from the chemical class of pulvinic acids, a validated ligand-based pharmacophore model was used in the screening of our in house virtual library, consisting of about two million commercially available compounds from the vendors Vitas-M and ChemDiv. The final pharmacophore model derived on the basis of four selected pulvinic acid derivatives was composed of 6 pharmacophore features: a hydrogen bond donor, three hydrogen bond acceptors, aromatic ring and an area of hydrophobic interactions. The features were surrounded by exclusion volume spheres to limit the space available for the investigated molecules (Fig 3). More details on the development of the pharmacophore model and its application in the virtual screening are provided in section 4.1.3.

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.