Abstract
Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.
Highlights
It was observed that daturaolone exhibited significant percent inhibition of TNF-α activated nuclear factor-κB (NF-κB) with a value of 92.17 ± 5.1% (IC50 : 1.2 ± 0.8 μg/mL), and the results are in justification with our studies, in which NF-κB was shown to form an interaction with the compound in molecular docking analysis
These results showed that daturaolone, being a potent inhibitor of Protein Kinase (PK), TNF-α activated NF-κB and nitric oxide (NO) production, is a noteworthy compound for the management of inflammatory disorders
Molecular target predictions and protein ligand interactions of daturaolone with cyclo-oxygenase 2 (COX-2), 5-LOX, estrogen receptor, dopamine receptor D1, phospholipase A2, 5-hydroxytryptamine, NF-κB and serotonin 2A receptor and serotonin transporter were determined according to previously stated protocol with slight modifications [38]
Summary
Pharmaceuticals 2021, 14, 1248 formation, blood coagulation via leukocyte adhesion, oxidative stress generation and in direct induction of fever Another important inflammatory mediator in the cascade is ni tric oxide (NO), the overproduction of which causes vasoconstriction, inflammation, tis sue damage and neurodegenerative disorders [2]. Plant-sourced pentacyclic oleanane triterpenoids are a class of compounds that, unlike conventional in signal transduction pathways of inflammation Their significant effects on changing the cytotoxic agents, are multifunctional that aim to act on molecularistargets redox state of tissues and cells leads to inflammation [3].unique.
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