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Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2013 May; Vol. 63, pp. 321-32. Date of Electronic Publication: 2013 Feb 24. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- 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
Molecular Sequence Data
Molecular Structure
Mutagenesis, Site-Directed
PPAR alpha agonists
PPAR alpha genetics
PPAR gamma agonists
PPAR gamma genetics
Phenylacetates chemistry
Phenylacetates pharmacology
Quantitative Structure-Activity Relationship
Thermodynamics
Models, Molecular
PPAR alpha chemistry
PPAR gamma chemistry
Protein Structure, Tertiary
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 63
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23502212
- Full Text :
- https://doi.org/10.1016/j.ejmech.2013.02.015