Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges

Sepe, Valentina; D’Amore, Claudio; Ummarino, Raffella; Renga, Barbara; D’Auria, Maria Valeria; Novellino, Ettore; Sinisi, Annamaria; Taglialatela‐Scafati, Orazio; Nakao, Yoichi; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano

doi:10.1016/j.ejmech.2013.12.005

Cited by 17 publications

(21 citation statements)

References 34 publications

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“…For these calculations, we used the crystal structure of the PXR-LBD in complex with the inhibitor SR-12813 (PDB code 3hvl), which has been successfully employed to investigate the binding of ligands with steroidal scaffold to PXR [33,34]. In the best-scored docking pose, the ligand occupies the binding site pointing its polar head towards the activation function-2 domain (AF-2, colored in orange in Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

et al. 2014

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In recent years many sterols with unusual structures and promising biological profiles have been identified from marine sources. Here we report the isolation of a series of 24-alkylated-hydroxysteroids from the soft coral Sinularia kavarattiensis, acting as pregnane X receptor (PXR) modulators. Starting from this scaffold a number of derivatives were prepared and evaluated for their ability to activate the PXR by assessing transactivation and quantifying gene expression. Our study reveals that ergost-5-en-3β-ol (4) induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target gene CYP3A4. To shed light on the molecular basis of the interaction between these ligands and PXR, we investigated, through docking simulations, the binding mechanism of the most potent compound of the series, 4, to the PXR. Our findings provide useful functional and structural information to guide further investigations and drug design.

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Section: Resultsmentioning

confidence: 99%

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

et al. 2014

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“…Table 2 reports new drugs and drug derivatives obtained by different marine organisms proposed in anti-obesity treatment [62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94]. …”

Section: Treatment Of Obesitymentioning

confidence: 99%

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

et al. 2017

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Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity effects and proposed potential mechanisms by which lung function can be modulated with the anti-obesity activity. Considering the similar mechanism, such as inflammation, shared between obesity and COPD, the study suggests that marine derivatives that act on the adipose tissues to reduce inflammation may provide beneficial therapeutic effects in COPD subjects with high body mass index (BMI).

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“…The experimental structures of PXR available have provided the basis for several computational investigations that mostly made use of molecular docking methods. These studies were focused on two aims: to find new drugs to either agonize or antagonize the PXR activity 5 , 23 – 25 ; and to model binding to some environmental pollutants 26 – 28 . For example, both ligand- and structure-based computational methods have been used to find novel modulators of PXR 5 , 24 , as well as to screen and predict toxic side-effects of xenobiotics 28 .…”

Section: Introductionmentioning

confidence: 99%

Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods

Motta

Callea

Tagliabue

et al. 2018

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The Pregnane X Receptor (PXR) is a ligand-activated transcription factor belonging to the nuclear receptor family. PXR can bind diverse drugs and environmental toxicants with different binding modes, making it an intriguing target for drug discovery. Here we investigated the binding mechanism of the SR12813 ligand to elucidate the significant steps, from the ligand entrance pathway into the binding cavity, to the ligand-induced conformational changes, and to the exploration of its alternative binding geometries. We used the advanced Molecular Dynamics-based methods implemented in the BiKi suite and developed specific methodological approaches to overcome the complexity induced by the buried and flexible binding cavity. The adopted methods provided a full dynamic description of the binding event and allowed rationalization of the observed multiple binding modes. These results suggest that the same approach could be exploited for the study of other binding processes with similar characteristics.

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Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges

Cited by 17 publications

References 34 publications

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

Marine and Semi-Synthetic Hydroxysteroids as New Scaffolds for Pregnane X Receptor Modulation

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives

Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods

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