Discovery of New Liver X Receptor Agonists by Pharmacophore Modeling and Shape-Based Virtual Screening

Agonists of liver X receptors (LXR) α and β are important regulators of cholesterol metabolism, but agonism of the LXRα subtype appears to cause hepatic lipogenesis, suggesting LXRβ-selective activators are attractive new lipid lowering drugs. In this work, pharmacophore modeling and shape-based virtual screening were combined to predict new LXRβ-selective ligands. Out of the 10 predicted compounds, three displayed significant LXR activity. Two activated both LXR subtypes. The third compound activated LXRβ 1.8-fold over LXRα

Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibitors by Pharmacophore-Based Virtual Screening

There is an increasing interest in the development of soluble epoxide hydrolase (sEH) inhibitors, which block the degradation of endogenous anti-inflammatory epoxyeicosatrienoic acids. Within this study, a set of pharmacophore models for sEH inhibitors was developed. The Specs database was virtually screened and a cell-free sEH activity assay was used for the biological investigation of virtual hits. In total, out of 48 tested compounds, 19 were sEH inhibitors with IC₅₀ < 10 μM, representing a prospective true positive hit rate of 40%. Six of these compounds displayed IC₅₀ values in the low nanomolar range. The most potent compound <b>21</b>, a urea derivative, inhibited sEH with an IC₅₀ = 4.2 nM. The applied approach also enabled the identification of diverse chemical scaffolds, e.g. the pyrimidinone derivative <b>29</b> (IC₅₀ = 277 nM). The generated pharmacophore model set therefore represents a valuable tool for the selection of compounds for biological testing

Anti-inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis

Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from <i>Paulownia tomentosa</i> fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (<b>17</b>) and tomentodiplacone O (<b>20</b>)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (<b>20</b>) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (<b>14</b>) (a major geranylated flavanone of <i>P. tomentosa</i>), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect

Anti-inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis

Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from <i>Paulownia tomentosa</i> fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (<b>17</b>) and tomentodiplacone O (<b>20</b>)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (<b>20</b>) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (<b>14</b>) (a major geranylated flavanone of <i>P. tomentosa</i>), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect

Anti-inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis

Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from <i>Paulownia tomentosa</i> fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (<b>17</b>) and tomentodiplacone O (<b>20</b>)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (<b>20</b>) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (<b>14</b>) (a major geranylated flavanone of <i>P. tomentosa</i>), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect