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.
Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists / A. Carrieri, M. Giudici, M. Parente, M. De Rosas, L. Piemontese, G. Fracchiolla, A. Laghezza, P. Tortorella, G. Carbonara, A. Lavecchia, F. Gilardi, M. Crestani, F. Loiodice. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 63(2013 May), pp. 321-332.
|Titolo:||Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists|
|Parole Chiave:||Models, Molecular ; Protein Structure, Tertiary ; Algorithms ; Amino Acid Sequence ; Binding Sites ; Binding, Competitive ; Clofibric Acid ; Computer Simulation ; Crystallography, X-Ray ; Hep G2 Cells ; Humans ; Hypolipidemic Agents ; Ligands ; Molecular Sequence Data ; Molecular Structure ; Mutagenesis, Site-Directed ; PPAR alpha ; PPAR gamma ; Phenylacetates ; Quantitative Structure-Activity Relationship ; Thermodynamics|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore CHIM/08 - Chimica Farmaceutica
|Data di pubblicazione:||mag-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejmech.2013.02.015|
|Appare nelle tipologie:||01 - Articolo su periodico|