Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.

Détails

ID Serval
serval:BIB_DCBFB59FC583
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.
Périodique
European Journal of Medicinal Chemistry
Auteur⸱e⸱s
Carrieri A., Giudici M., Parente M., De Rosas M., Piemontese L., Fracchiolla G., Laghezza A., Tortorella P., Carbonara G., Lavecchia A., Gilardi F., Crestani M., Loiodice F.
ISSN
1768-3254 (Electronic)
ISSN-L
0223-5234
Statut éditorial
Publié
Date de publication
2013
Peer-reviewed
Oui
Volume
63
Pages
321-332
Langue
anglais
Résumé
A series of previously synthesized chiral derivatives of clofibric and phenylacetic acids, acting as dual agonists towards the peroxisome proliferator-activated receptors (PPARs) α and γ, was taken into account, and the efficacy of these compounds was analyzed by means of 2D-, 3D-QSAR and docking studies with the goal to gain deeper insights into the three-dimensional determinants governing ligands selectivity for PPARs. By multiregressional analysis a correlation between the lipophilicity and PPARα activity was found, whereas for PPARγ the correlation was achieved once efficacy was related to the presence of polar groups on agonists scaffold. Docking of these compounds further corroborated this hypothesis, and then provided a valid support for subsequent chemometric analysis and pharmacophore models development for both receptors subtypes. Computational results suggested site directed mutagenesis experiments which confirmed the importance of amino acid residues in PPAR activity, allowing the identification of critical hotspots most likely taking over PPARs selectivity.
Mots-clé
Algorithms, Amino Acid Sequence, Binding Sites/genetics, Binding, Competitive, Clofibric Acid/chemistry, Clofibric Acid/pharmacology, Computer Simulation, Crystallography, X-Ray, Hep G2 Cells, Humans, Hypolipidemic Agents/chemistry, Hypolipidemic Agents/pharmacology, Ligands, Models, Molecular, Molecular Sequence Data, Molecular Structure, Mutagenesis, Site-Directed, PPAR alpha/agonists, PPAR alpha/chemistry, PPAR gamma/agonists, PPAR gamma/chemistry, Phenylacetates/chemistry, Phenylacetates/pharmacology, Protein Structure, Tertiary, Quantitative Structure-Activity Relationship, Thermodynamics
Pubmed
Web of science
Création de la notice
15/02/2015 21:39
Dernière modification de la notice
17/02/2020 17:28
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