52 research outputs found
Frontal Affinity Chromatography with MS detection of the ligand binding domain of PPAR-gamma receptor: ligand affinity screening and stereoselective ligand-macromolecule interaction
No full textAffinity-based separation methods for the study of biological interactions: The case of peroxisome proliferator-activated receptors in drug discovery
No full textAffinity-based methods using immobilized proteins are important approaches for understanding the
interactions between small molecules and biological targets. This review is intended to provide an overview
of different affinity based separation methods that have been applied to the study of peroxisome
proliferator activated receptors (PPARs). The screening of compound to increase screening rates for synthetic
and natural ligands of PPAR are reported. Pros and cons of the approaches in ligand discovery initiatives
are discusse
On the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands
No full textFrontal affinity chromatography with MS detection used in the screening of PPARgamma receptor agonists and to study the stereoselective interaction with the Ligand Binding Domain
No full textStructural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates
No full textPochetti G, Gavuzzo E, Campestre C, et al. Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. JOURNAL OF MEDICINAL CHEMISTRY. 2006;49(3):923-931.Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed
Biointeraction Analysis by High Performance Frontal Affinity Chromatography: Immobilized PPAR gamma receptor
No full textFrontal affinity chromatography with MS detection: strategy and realization of immobilized PPARgamma receptor open tubular column for ligand affinity screening and stereoselective ligand-macromolecule interaction.
No full text
Screening of saponins and sapogenins from Medicago species as potential PPARγ agonists and X-ray structure of the complex PPARγ/caulophyllogenin
No full textA series of saponins and sapogenins from Medicago species were tested for their ability to bind and activate the nuclear receptor PPARγ by SPR experiments and transactivation assay, respectively. The SPR analysis proved to be a very powerful and fast technique for screening a large number of compounds for their affinity to PPARγ and selecting the better candidates for further studies. Based on the obtained results, the sapogenin caulophyllogenin was proved to be a partial agonist towards PPARγ and the X-ray structure of its complex with PPARγ was also solved, in order to investigate the binding mode in the ligand binding domain of the nuclear receptor. This is the first known crystal structure of a sapogenin directly interacting with PPARγ. Another compound of the series, the echinocistic acid, showed antagonist activity towards PPARγ, a property that could be useful to inhibit the adipocyte differentiation which is a typical adverse effect of PPARγ agonists. This study confirms the interest on saponins and sapogenins as a valuable natural resource exploitable in the medical and food industry for ameliorating the metabolic syndrome
Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode
No full textThe peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARλ 3 full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARλ 3, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARλ 3 provides a rationale for the different activation of the ligand towards PPARα and PPARλ 3, suggesting a novel basis for ligand design
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