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![Structural basis of nuclear receptor ligand binding and cofactor recruitment. The structures shown here are the LBD of RXR (green image in the diagram). ( A ) Apo-RXR (no ligand bound, PDB 1LBD) [72]; ( B ) RXR complexed with agonist BMS649 (PDB 2ZY0) [73]; ( C ) RXR complexed with corepressor SMRT (silencing mediator for retinoid or thyroid-hormone receptors) (PDB 3R29) [74]. The agonist, coactivator, and corepressor are depicted as orange space filling spheres, a red image, and a yellow image, respectively. When an agonist is bound to a NR, the C -terminal α helix of the LBD (AF-2, blue) changes its position so that a coactivator protein (red) can bind to the surface of the LBD ( B ). Antagonist occupies the same ligand-binding cavity of the NR (antagonist not shown). However, antagonist ligands in addition have a side chain extension, which sterically pushes AF-2 to move towards outside, and corepressor (yellow) occupies roughly the same position in space as coactivators bind. Hence, coactivator binding to the LBD is blocked.](profile/Chunyan-Yang-5/publication/259959570/figure/fig2/AS:297196269391881@1447868520680/Structural-basis-of-nuclear-receptor-ligand-binding-and-cofactor-recruitment-The.png)
Structural basis of nuclear receptor ligand binding and cofactor recruitment. The structures shown here are the LBD of RXR (green image in the diagram). ( A ) Apo-RXR (no ligand bound, PDB 1LBD) [72]; ( B ) RXR complexed with agonist BMS649 (PDB 2ZY0) [73]; ( C ) RXR complexed with corepressor SMRT (silencing mediator for retinoid or thyroid-hormone receptors) (PDB 3R29) [74]. The agonist, coactivator, and corepressor are depicted as orange space filling spheres, a red image, and a yellow image, respectively. When an agonist is bound to a NR, the C -terminal α helix of the LBD (AF-2, blue) changes its position so that a coactivator protein (red) can bind to the surface of the LBD ( B ). Antagonist occupies the same ligand-binding cavity of the NR (antagonist not shown). However, antagonist ligands in addition have a side chain extension, which sterically pushes AF-2 to move towards outside, and corepressor (yellow) occupies roughly the same position in space as coactivators bind. Hence, coactivator binding to the LBD is blocked.
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Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting an...
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Context 1
... ligand binding, which induces a conformational change in the receptor; thus, the ligand-binding pocket is an important structural feature of nuclear receptors. Upon the binding of an agonist, nuclear receptors use a charge clamp pocket, in part composed of the C -terminal AF-2 helix, to form a hydrophobic groove for binding of the LXXLL motif of coactivators, such as SRCs (steroid receptor coactivators) and GRIP1 (glucocorticoid receptor interacting protein 1), leading to the modulation and promotion of gene transcription (Figure 1D). Antagonists block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. Therefore, the antagonist-bound receptor is in an inactive state and preferentially binds corepressor proteins, leading to the repression of gene transcription [77,78]. The corepressors bind to LBDs via a conserved LXXXIXXXL/I motif, which is longer than LXXLL coactivator motif and adopts a three- turn α helix. The binding of corepressor motif induces major conformation change of AF-2 helix to accomadate the larger corepressor helix. The conformational flexibility of AF-2 helix allows the NR to sense the presence of the bound ligand, either an agonist or an antagonist, and to recruit the coactivator or corepressors that ultimately determine the transcriptional activation or repression of NRs (Figure 2) [8]. There is a pressing need to develop detailed structure – function relationships (SAR) of nuclear receptor and ligand interaction to facilitate the discovery of potent ligands. Structural comparison and analysis show that several features of the ligand-binding pocket have contributed to the ligand binding affinity and specificity. The ligand-binding pocket is the least conserved region on LBD, in which size and shape varies greatly from receptor subtype to subtype, to further accommodate specific ligands. The small pocket seen in the ERRα (estrogen-related receptor α ) suggests that only ligands with four to five carbon atoms or less can fit [79]. In contrast, the large pocket in PXR (pregnane X receptor) allows the binding of antibiotic rifampicin, one of the largest structural ligands for nuclear receptors [80]. The overall hydrophobic nature of the ligand-binding pocket allows the NRs to interact with many lipid soluble ligands [81,82]. Given the plastic nature of the ligand-binding pockets, NRs respond differently to distinct ligands and readily exchange their ligands in different environments. From the drug discovery point of view, NRs may possess even greater potential as the flexible ligand-binding pocket allowing them to interact with a wider array of pharmacophores. As such, the ligand-binding pockets of nuclear receptors are promising sites for drug discovery research. NR dimerization is critical in many regulatory processes, as NRs can bind to their cognate sequence-specific promoter elements on target genes either as monomers [83 – 86], homodimers [72,87 – 93], or heterodimers with RXRs (retinoid X receptor α, β, and γ) [75,94 – 100] (Figure 1D). Cooperative DNA binding and distinct recognition sites of homodimer and heterodimer make dimerization a general mechanism to increase binding site affinity, specificity, and diversity [101]. NR LBD stabilizes the dimers, while NR DBD contributes to response element selection by dictating the response element repertoire for monomer, homodimer, or heterodimer receptors. The steroid receptors appear to function as homodimers, such as ER (estrogen receptor) [88], PR (progesterone receptor) [102], AR (androgens receptor) [103], GR (glucocorticoids receptor) [93], and MR (mineralocorticoid receptor) [71]. HNF4 α (Hepatocyte nuclear factor 4 alpha) is rather unique in that it binds DNA exclusively as a homodimer and, yet, behaves as the subtype nuclear receptors that localized primarily in the nucleus and usually activated as heterodimer with RXR [92]. One third of known NRs act as heterodimers with RXR, including RARs (retinoic acid receptors) [94,95], VDR (vitamin D receptors) [104,105], TR (thyroid hormone receptors) [96], LXR (liver X receptor) ...
Context 2
... nuclear receptors exhibit similar structural features (Figure 1B). Nuclear receptor LBD structures contain 11 – 13 α -helices that are arranged into a three-layer antiparallel α -helical sandwich [75,76]. The three long helices (H3, 7, and 10) form the two outer layers, and the middle layer of helices (H5, 6, 8, and 9) is present only in the top half of the domain, thereby creating a cavity for ligand binding, the so-called ligand-binding pocket (Figure 1C). The AF-2 also forms a helix that can adopt multiple conformations depending on different bound ligands (Figure 2). The first step of nuclear receptor activation is ...
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Citations
... The current study's findings indicated that both of the leads (epi-magnolin (3) and colchicine) had strong bioactivity scores, with enzyme inhibitor showing values more than 0.00. Since nuclear receptors (NRs) are essential regulators of several inflammatory and metabolic disorders, including as diabetes, dyslipidemia, cirrhosis, and fibrosis, they are valuable targets for pharmacological development (Yang et al., 2014). Alternatively, and in light of the findings, Table S3 shows that epi-Magnolin (3) and colchicine had moderate activity for NRs, GPCR, ion channel modulators, kinase inhibitors, and protease inhibition. ...
Five known furofuran lignans, dia-sesamin (1), 5-methoxysesamin (2), epi-magnolin (3), kobusin (4) and yangambin (5) were isolated for the first-time from the oleo-gum resin of Commiphora wightii. This is the first report on the 13C NMR assignments for epi-magnolin (3). Each of the isolated compounds was
evaluated for its ability to inhibit MIA PaCa-2 pancreatic cancer cell line. Among them, epi-magnolin (3) displayed potential activity (IC50 ¼ 29 nM) compared to colchicine (IC50 ¼ 56 nM). 3D-flexible alignment revealed that epi-magnolin (3) has great matching with the tubulin polymerization inhibitor, colchicine. Meanwhile, docking studies exhibited that compounds 1–5 displayed good binding free
energies against colchicine binding site (CBS) of tubulin with binding modes that were highly comparable to that of colchicine. Compounds 2, 3, and 5 showed superior binding free energies than colchicine (-24.37 kcal/mol). epi-Magnolin (3) showed the highest binding score against CBS. MD simulation
studies confirmed the stability of epi-magnolin (3) in the active site for 200 ns. Furthermore, four online servers (Swiss ADME, pkCSM pharmacokinetics, AdmetSAR, and ProTox-II) were utilized to predict the ADMET parameters. The in-silico pharmacokinetics predictions reveled that epi-magnolin (3)
has significant oral bioavailability and drug-like capabilities.
... Sequences of NRs share considerable homology and conserved structures, which are divided into six subregions, as shown in Figure 1 [2,14]. The N-terminal region involves A/B subregions and has a ligand-independent activation function (AF1). ...
... This happens through recruiting a specific cofactor and binding to a specific DNA-response element (RE) in the corresponding target gene [2]. Imitating the endogenous hydrophobic ligand with a synthetic one that can interact with the LBD is a common approach to modulating NRs' pharmacological pathways [14,16,17]. The action of ligands is more complicated than it seems, as it occurs in a tissue-specific manner, i.e., the cellular context and type of the recruited cofactor determines the resulting activity. ...
... This happens through recruiting a specific cofactor and binding to a specific DNAresponse element (RE) in the corresponding target gene [2]. Imitating the endogenous hydrophobic ligand with a synthetic one that can interact with the LBD is a common approach to modulating NRs' pharmacological pathways [14,16,17]. The action of ligands is more complicated than it seems, as it occurs in a tissue-specific manner, i.e., the cellular context and type of the recruited cofactor determines the resulting activity. ...
Nuclear receptors (NRs) form a family of druggable transcription factors that are regulated by ligand binding to orchestrate multifaceted physiological functions, including reproduction, immunity , metabolism, and growth. NRs represent attractive and valid targets for the management and treatment of a vast array of ailments. Pentacyclic triterpenes (PTs) are ubiquitously distributed natural products in medicinal and aromatic plants, of which ursolic acid (UA) is an extensively studied member, due to its diverse bio-pertinent activities against different cancers, inflammation, aging, obesity, diabetes, dyslipidemia, and liver injury. In fact, PTs share a common lipophilic structure that resembles NRs' endogenous ligands. Herein, we present a review of the literature on UA's effect on NRs, showcasing the resulting health benefits and potential therapeutic outcomes. De facto, UA exhibited numerous pharmacodynamic effects on PPAR, LXR, FXR, and PXR, resulting in remarkable anti-inflammatory, anti-hyperlipidemic, and hepatoprotective properties, by lowering lipid accumulation in hepatocytes and mitigating non-alcoholic steatohepatitis (NASH) and its subsequent liver fibrosis. Furthermore, UA reversed valproate and rifampicin-induced hepatic lipid accumulation. Additionally, UA showed great promise for the treatment of autoimmune inflammatory diseases such as multiple sclerosis and autoimmune arthritis by antagonizing RORγ. UA exhibited antiproliferative effects against skin, prostate, and breast cancers, partially via PPARα and RORγ pathways. Herein, for the first time, we explore and provide insights into UA bioactivity with respect to NR modulation.
... De facto, many natural products of both plant and marine origin have been proven effective with respect to NRs modulation [18][19][20][49][50][51][52]. Theonellasterol is a natural sterol from a marine sponge with an FXR antagonistic effect and protective properties against cholestasis-induced liver injury [53]. ...
... PPARγ has a significant role in controlling insulin sensitivity and adipogenesis [94]. Fibrates and thiazolidinedione are two classes of PPARs modulators approved for hyperlipidemia and diabetes therapy, respectively [19]. Fibrates such as pemafibrate modulate PPARα, whereas thiazolidinediones such as rosiglitazone upregulate PPARγ [95]. ...
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
... This is via recruiting a coregulator that activates, in case of agonist, or suppresses, in case of antagonist, gene transcription. The ligand-binding pocket is the least conserved region on LBD, which makes it the main target for NR modulation [20][21][22] . It is noteworthy that the resulting activation of a coactivator or corepressor occurs in a tissue-specific manner, which makes it more complex to obtain a selective NR modulator. ...
... De facto, many natural products of both plant and marine origin have been proven effective with respect to NRs modulation [19][20][21][50][51][52][53] . Theonellasterol is a natural sterol from a marine sponge with an FXR antagonistic effect and protective properties against cholestasis-induced liver injury 54 . ...
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to those NRs modulation, OA exhibited prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
... Preconicasterol (27), featuring a ∆ 24 double bond, represents the first example of 4-methylene steroid without any branching in the side chain [21] while dehydroconicasterol (25) shows an additional exo-methylene group at C-24 [22]. As reported in Figure 4, preconicasterol (27) should be considered the biogenetic precursor of the branched dehydroconicasterol (25) that, in turn, subjected to reduction and/or transmethylation with S-adenosylmethionine, led to the formation of conicasterol (2) or theonellasterol (1) [21]. ...
... As reported in Figure 4, preconicasterol (27) should be considered the biogenetic precursor of the branched dehydroconicasterol (25) that, in turn, subjected to reduction and/or transmethylation with S-adenosylmethionine, led to the formation of conicasterol (2) or theonellasterol (1) [21]. Preconicasterol (27), featuring a Δ 24 double bond, represents the first example of 4methylene steroid without any branching in the side chain [21] while dehydroconicasterol (25) shows an additional exo-methylene group at C-24 [22]. As reported in Figure 4, preconicasterol (27) should be considered the biogenetic precursor of the branched dehydroconicasterol (25) that, in turn, subjected to reduction and/or transmethylation with S-adenosylmethionine, led to the formation of conicasterol (2) or theonellasterol (1) [21]. ...
... Indeed, the presence of an ancestral NR has been demonstrated in sponges, the simplest animal organisms, and it is well recognized that there is a close relationship between the complexity of the organism and the diversification of the genes encoding for NR. Moreover, during the evolution along the metazoan tree, both changes in the structural organization of the receptors and their corresponding ligands occurred [25]. ...
The marine environment is considered a vast source in the discovery of structurally unique bioactive secondary metabolites. Among marine invertebrates, the sponge Theonella spp. represents an arsenal of novel compounds ranging from peptides, alkaloids, terpenes, macrolides, and sterols. In this review, we summarize the recent reports on sterols isolated from this amazing sponge, describing their structural features and peculiar biological activities. We also discuss the total syntheses of solomonsterols A and B and the medicinal chemistry modifications on theonellasterol and conicasterol, focusing on the effect of chemical transformations on the biological activity of this class of metabolites. The promising compounds identified from Theonella spp. possess pronounced biological activity on nuclear receptors or cytotoxicity and result in promising candidates for extended preclinical evaluations. The identification of naturally occurring and semisynthetic marine bioactive sterols reaffirms the utility of examining natural product libraries for the discovery of new therapeutical approach to human diseases.
... Natural compounds derived from marine organisms have been valued for over half a century, but growing interest in this promising novel natural medication has only recently emerged. Numerous unique compounds that modulate NRs have been discovered by chemical, structural, and pharmacological characterizations of marine natural resources [514]. Marine sponges and tunicates have been proven to be an outstanding source of novel chemical entities with antiinfectious, anti-inflammatory anti-oxidant, and anti-cancer activities [514,515]. ...
... Numerous unique compounds that modulate NRs have been discovered by chemical, structural, and pharmacological characterizations of marine natural resources [514]. Marine sponges and tunicates have been proven to be an outstanding source of novel chemical entities with antiinfectious, anti-inflammatory anti-oxidant, and anti-cancer activities [514,515]. Mora et al. demonstrated that marine sponge Pseudoceratina rhax metabolite psammaplin A of 10 μM concentration induces apoptosis in MCF-7 breast cancer cell lines by activating PPARγ within 10 h of treatment [418]. A bioactive compound sintokamide A extracted from Dysidea species of marine sponge showed potent AR inhibitory activity when treated for one hour at a concentration of 5 μg/mL in LNCaP prostate cancer cell lines [419]. ...
... The figure was created in BioRender.com anti-cancer properties under various clinical and preclinical trials [514,515]. Several studies have shown that tunicate-derived compounds modulate nuclear receptors at the molecular level in cancer cells. For instance, Imperatore et al. showed that phallusiasterols A (10 μM) and B (10 μM) isolated from the tunicate, Phallusia fumigata, transactivate PXR and induce the downstream target genes CYP3A4 and MDR1 in hepatocellular carcinoma cell lines [441]. ...
Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly–derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.
... Nuclear receptors are key regulators of various metabolic diseases such as diabetes. 44 Based on our results, all compounds showed active (compound 1, 3, 5, 6, 7 and 8) to moderate (compound 2 and 4) potential to inhibit nuclear receptors. This implies that these compounds are promising therapeutic alternatives to treat some metabolic disorders. ...
Computational Evaluation of ADMET Properties and Bioactive Score of Compounds from Encephalartos ferox
... Nuclear receptors are key regulators of various metabolic diseases such as diabetes. 44 Based on our results, all compounds showed active (compound 1, 3, 5, 6, 7 and 8) to moderate (compound 2 and 4) potential to inhibit nuclear receptors. This implies that these compounds are promising therapeutic alternatives to treat some metabolic disorders. ...
Background: Plant-based products are recognized as sources of drugs for the treatment of diseases. Objective: The study aimed at predicting the physicochemical, pharmacokinetics, drug-likeness, and toxicity of the compounds identified from the methanolic Encephalartos ferox fruit extract. Methods: The physicochemical, pharmacokinetics properties and bioactive scores of the compounds were predicted using SwissADME and Molinspiration computational tools. Drug-likeness of the compounds was evaluated based on the Lipinski rule of five (Ro5). In silico mutagenicity, carcinogenicity, and inhibition of the human ether-a-go-go-related (hERG) gene were also investigated using PreADMET web tool. Results: The physicochemical properties showed the compounds, except 9-Octadecenoic acid, 1, 2, 3-propanetriyl ester to adhere to Ro5. The evaluation of their inhibitory effects profile in several cytochrome P450 isoforms indicates that all the compounds are not the inhibitors of CYP2C19 and CYP3A4 whereas some inhibited CYP1A2, CYP2C9 and CYP2D6. The drug-likeness evaluation employed Ro5 as a filter and all compounds complied with it except for 9-Octadecenoic acid, 1, 2, 3-propanetriyl ester. About 50% of the tested compounds were found to be safe as they did not exhibit antimutagenic and carcinogenic effects. Moreover, the risk of inhibition of hERG gene was revealed to be low to medium risk depending on the compound. Conclusion: The calculated physicochemical and pharmacokinetic properties suggest that most of the compounds are safe and have promising oral bioavailability.
Key words: Compounds, Pharmacokinetic; Drug-likeness, Bioactive score, Toxicity.
... 30 Recently, the rise of metabolic diseases such as obesity and diabetes has caused a resurging interest in modulating energy expenditure through NRs. 31 NRs are ubiquitous in animals, and hundreds of natural products have been reported to alter their functions. [32][33][34] Certain NRs are particularly susceptible to modulation by natural products, such as the oestrogen receptor or the peroxisome proliferator-activated receptor g (PPARg). 35 On the other hand, there have been virtually no reports of natural product modulators of thyroid hormone receptors, although synthetic modulators exist. ...
Humans perceive physical information about the surrounding environment through their senses. This physical information is registered by a collection of highly evolved and finely tuned molecular sensory receptors. A multitude of bioactive, structurally diverse ligands have evolved in nature that bind these molecular receptors. The complex, dynamic interactions between the ligands and the receptors lead to changes in our sensory perception or mood. Here, we review our current knowledge of natural products and their derived analogues that interact specifically with human G protein-coupled receptors, ion channels, and nuclear hormone receptors to modulate the sensations of taste, smell, temperature, pain, and itch, as well as mood and its associated behaviour. We discuss the molecular and structural mechanisms underlying such interactions and highlight cases where subtle differences in natural product chemistry produce drastic changes in functional outcome. We also discuss cases where a single compound triggers complex sensory or behavioural changes in humans through multiple mechanistic targets. Finally, we comment on the therapeutic potential of the reviewed area of research and draw attention to recent technological developments in genomics, metabolomics, and metabolic engineering that allow us to tap the medicinal properties of natural product chemistry without taxing nature.
... with Astragalin and Quercetin 7 being the most active as EIs (0.41 and 0.42, respectively) and Quercetin being the most active as KI and NRL (Table II). Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis and fibrosis (Yang, Li, Li, 2014). Based on our results, quercetin, qstragalin and quercetin 7 could be envisioned as potential ligands for NRs representing interesting and promising therapeutic alternatives to cure relevant disorders. ...
In-silico study was performed to find the pharmacodynamics, toxicity profiles and biological activities of three phytochemicals isolated from Limoniastrum feei (Plumbagenaceae). Online pharmacokinetic tools were used to estimate the potential of Quercetin, kaempferol-3-O-β-D-glucopyranoside (astragalin) and quercitin-7-O-β-D-glucopyranoside as specific drugs. Then the prediction of potential targets of these compounds were investigated using PharmMapper. Auto-Dock 4.0 software was used to investigate the different interactions of these compounds with the targets predicted earlier. The permeability of quercetin was found within the range stated by Lipinski ׳s rule of five. Hematopoietic prostaglandin (PG) D synthase (HPGDS), farnesyl diphosphate synthetase (FPPS) and the deoxycytidine kinase (DCK) were potential targets for quercetin, astragalin and quercetin 7, respectively. Quercetin showed antiallergic and anti-inflammatory activity, while astragalin and quercetin 7 were predicted to have anticancer activities. The activity of Astragalin appeared to be mediated by FPPS inhibition. The inhibition of DCK was predicted as the anticancer mechanisms of quercetin 7. The compounds showed interesting interactions and satisfactory binding energies when docked into their targets. These compounds are proposed to have activities against a variety of human aliments such as allergy, tumors, muscular dystrophy, and diabetic cataracts.
