title: Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.
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.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli studi di Bari 'Aldo Moro', via E. Orabona 4, 70125 Bari, Italy. antonio.carrieri@uniba.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Marco
authors.initials: M
authors.lastname: Giudici
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Parente
authors.forename: Mario
authors.initials: M
authors.lastname: De Rosas
authors.forename: Luca
authors.initials: L
authors.lastname: Piemontese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Federica
authors.initials: F
authors.lastname: Gilardi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D002995:Clofibric Acid / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D056945:Hep G2 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D047493:PPAR alpha / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000960:Hypolipidemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010648:Phenylacetates; D002995:Clofibric Acid