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

Details

Serval ID
serval:BIB_DCBFB59FC583
Type
Article: article from journal or magazin.
Collection
Publications
Title
Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.
Journal
European Journal of Medicinal Chemistry
Author(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
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
63
Pages
321-332
Language
english
Abstract
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.
Keywords
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
Create date
15/02/2015 21:39
Last modification date
17/02/2020 17:28
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