Molecular determinants of PPARγ partial agonism and related in silico/in vivo studies of natural saponins as potential type 2 diabetes modulators

Sharif, Merilin Al; Alov, Petko; Diukendjieva, Antonia; Vitcheva, Vessela; Simeonova, Rumyana; Krasteva, Ilina; Shkondrov, Aleksandar; Tsakovska, Ivanka; Pajeva, Ilza

doi:10.1016/j.fct.2017.12.009

Cited by 10 publications

(7 citation statements)

References 86 publications

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“…During the UHPLC separation optimization, mobile phases similar to those reported previously [22] were used. The separation was three times faster compared to the conventional HPLC, and approx.…”

Section: Methods Validationmentioning

confidence: 99%

Production of saponins from in vitro cultures of Astragalus glycyphyllos and their antineoplastic activity

Shkondrov

Krasteva

Йонкова

et al. 2019

Biotechnology & Biotechnological Equipment

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In the last decade the need of plant-derived cytotoxic compounds exceeds the possibilities for obtaining them from naturally grown sources. In vitro plant biotechnology offers a unique and often invaluable alternative for production of complex biologically active substances without harming the flora. Astragalus glycyphyllos L. (Fabaceae) is a plant native to Bulgaria that has been reported to contain triterpenoid saponins and flavonoids. It is used in folk medicine as an antihypertensive, diuretic, anti-inflammatory, anti-tumour, laxative, expectorant agent, etc. The aim was to study the saponin content of A. glycyphyllos cultures grown in vitro and their antiproliferative activity. Three types of cultures were developed: callus, shoot and suspension cultures. Murashige and Skoog's, as well as other media, supplemented with various concentrations and combinations of plant growth regulators and different photoperiods were used. In all cultures the saponin content was determined by a novel liquid chromatography-mass spectrometry (LC-MS) method. Compared to the wild grown species, in vitro shoot cultures accumulated double the amount of the main saponin (225.00 ng/mg dw) found in the plant. Saponin-rich fractions obtained from shoot cultures were tested for cytotoxicity in a panel of various malignant human cells and half-maximal inhibitory concentration (IC 50) values were determined. Interestingly, the saponin-rich fractions showed higher efficacy against urinary bladder cancer cells with constitutive high expression level of the xenobiotic pump gp170 (MDR1). In vitro cultures of A. glycyphyllos could serve as an alternative way for production of saponins, with promising antineoplastic activity, which deserves further detailed characterization.

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Section: Methods Validationmentioning

confidence: 99%

Production of saponins from in vitro cultures of Astragalus glycyphyllos and their antineoplastic activity

Shkondrov

Krasteva

Йонкова

et al. 2019

Biotechnology & Biotechnological Equipment

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“…The structural information was retrieved from the NIH PubChem system or from literature sources [16]. The PDB was used as a source of X-ray complexes of human PPARγ and its ligands with weak partial agonistic activity (Emax ≤ 35% [2]) [17]. The corresponding ligands were extracted from the complexes, while the available structural and biological data for homologue series of their chemical analogues were retrieved from the literature [15].…”

Section: Data Extraction and Organizationmentioning

confidence: 99%

“…Virtual library of PPARγ weak partial agonists In total, 125 structures were collected and the corresponding biological data for transactivation activity (EC50, µM) and relative maximal activation (relative efficacy, Emax, %) were harvested (Supplementary Table 1). A previously established maximal relative efficacy threshold value of Emax ≤ 35% [2] was used as an inclusion criterion for the preparation of a virtual library with known PPARγ weak partial agonists. The virtual library contains weak partial agonists either extracted from PPARγ-ligand complexes in PDB (26 compounds) or retrieved from reported in the literature homologue series of these PDB ligands (99 compounds).…”

Section: Development Of Virtual Libraries Of Compoundsmentioning

confidence: 99%

“…1 Prevailing binding regions of the full (A) and weak partial agonists (B) of PPARγ identified by analysis of PDB complexes of the receptor ligand-binding domain [2] Treatment with PPARγ full agonists has been associated with adverse effects [9], therefore a paradigm has currently shifted toward development of partial agonists [5]. In our previous studies we discriminated weak from strong PPARγ partial agonists reported in the Protein Data Bank (PDB) by analysis of their protein-ligand interaction fingerprints, receptor binding modes and relative efficacies and developed pharmacophores for the two classes of agonists [2]. The pharmacophore of the weak partial agonists has been applied to screen triterpenoids derived from medicinal plants of the genus Astragalus [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…In our previous studies we discriminated weak from strong PPARγ partial agonists reported in the Protein Data Bank (PDB) by analysis of their protein-ligand interaction fingerprints, receptor binding modes and relative efficacies and developed pharmacophores for the two classes of agonists [2]. The pharmacophore of the weak partial agonists has been applied to screen triterpenoids derived from medicinal plants of the genus Astragalus [2,3]. Prediction of possibly coexisting reactive metabolites of an orally administrated compound, which could be produced by Phase I biotransformations, has been shown to allow for a detailed and physiologically relevant in silico study of its potential therapeutic modes of action by elucidation of diverse receptor binding patterns [3].…”

Section: Introductionmentioning

confidence: 99%

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2021

Int J Bioautomation

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Triterpenoids are well known metabolic syndrome (MetS) modulators. One of the suggested molecular mechanisms of action involves peroxisome proliferator-activated receptor gamma (PPARγ) activation. In this study we aimed to: (i) develop a virtual screening (VS) protocol for PPARγ weak partial agonists, (ii) predict potential metabolic transformations of naturally-derived triterpenoids, and (iii) perform VS of the triterpenoids and their metabolites. The NIH PubMed system was searched for publications about naturallyderived oleanane triterpenoids which are agonists or up-regulators of PPARγ. Structureand ligand-based methods were combined in the development of the VS protocol. Metabolites were predicted using Meteor Nexus expert system (Lhasa Limited). Two in-house virtual libraries of PPARγ weak partial agonists and naturally-derived triterpenoids with their predicted metabolites were compiled. The pharmacophore-based docking protocol was applied for VS of the collected triterpenoids. Most of the docking poses reproduced the binding mode of caulophyllogenin (a weak partial agonist) in a complex with PPARγ (PDB ID 5F9B). Our results contribute to the mechanistic explanation of the effects of triterpenoids suggesting possible weak partial agonistic activity toward PPARγ. This research can direct further studies on triterpenoids' role in MetS modulation. The developed protocol can be applied for VS of any PPARγ weak partial agonists.

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