article · Pharmaceuticals
This study examined the chemical makeup and medicinal potential of essential oil extracted from Corymbia citriodora leaves. Researchers compared standard steam distillation with microwave-assisted steam distillation, finding that the microwave method produced higher concentrations of oxygenated monoterpenes, particularly citronellal. Using gas chromatography and tandem mass spectrometry, they identified 63 chemical constituents. Computational screening then evaluated these molecules against key enzymes involved in chronic inflammation: cyclooxygenase-2, cyclooxygenase-1, and inducible nitric oxide synthase. A sesquiterpene named (Z,Z,Z)-1,5,9,9-tetramethyl-1,4,7-cycloundecatriene demonstrated the strongest computational binding to cyclooxygenase-2. Advanced molecular simulations and theoretical calculations confirmed that this compound formed stable complexes with the enzyme. In silico pharmacological profiling predicted high human intestinal absorption alongside a low risk of mutagenicity, liver toxicity, or cardiotoxicity. However, because it also bound strongly to cyclooxygenase-1, physical laboratory validation is required to evaluate selectivity.
Chronic inflammation contributes to numerous serious human illnesses, but existing pharmaceutical treatments often carry significant cardiovascular and gastrointestinal risks. Discovering stable, naturally derived compounds that target inflammatory enzymes can guide the development of safer alternatives. Demonstrating efficient extraction methods also aids in standardising plant-based chemical profiles for medicinal research.
This research is at an early computational stage. It could inform pharmaceutical developers and natural product chemists seeking multi-target anti-inflammatory lead structures, as well as essential oil producers optimising microwave extraction parameters for citronellal-rich outputs. Real-world drug development remains distant, as the lead molecule requires comprehensive in vitro enzymatic testing, cellular validation, and chemical optimisation to verify safety and isoform selectivity.
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Background/Objectives: Chronic inflammation sustained by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) underlies many human diseases, while the cardiovascular liabilities of coxibs have renewed interest in plant-derived alternatives. This study characterised the volatile composition of Corymbia citriodora essential oil under two distillation regimes and identified constituents able to inhibit human COX-2 and iNOS. Methods: Oils obtained by steam distillation (SD) and microwave-assisted steam distillation (MSD) were profiled by GC–MS/MS. All identified constituents were screened with SASA Vina against human COX-2 (PDB: 5KIR, 3LN1), ovine COX-1 (4COX) and human iNOS (3E7G), with native-ligand re-docking validating each protocol (RMSD 0.39–0.84 Å). The lead compound underwent density functional theory (B3LYP/3-21G/CPCM), 100 ns all-atom molecular dynamics, MM/GBSA and MM/PBSA decomposition, and pkCSM ADMET prediction. Results: Sixty-three constituents were identified (99.85% SD; 99.97% MSD). MSD enriched oxygenated monoterpenes (93.23% versus 88.27%), citronellal rose from 38.24% to 48.41%. (Z,Z,Z)-1,5,9,9-Tetramethyl-1,4,7-cycloundecatriene ranked highest at COX-2 (−8.0 to −8.2 kcal/mol) and also bound COX-1 (−8.8 kcal/mol) and iNOS (−6.8 kcal/mol). DFT indicated high kinetic stability (ΔE = 6.12 eV; η = 3.06 eV) and purely non-covalent hydrophobic binding. The COX-2 complex remained stable over 100 ns (Cα RMSD 0.17 ± 0.02 nm), with MM/GBSA and MM/PBSA binding energies of −23.98 and −21.95 kcal/mol and Val523 as the principal hotspot. ADMET prediction returned 96.61% human intestinal absorption and no mutagenicity, hepatotoxicity or hERG I blockade. Conclusions: MSD offers a faster route to a citronellal-enriched oil, and C. citriodora hydrocarbon sesquiterpenes emerge as chemically stable, multi-target COX-2/iNOS scaffolds. Comparable binding at COX-1 indicates that isoform selectivity remains to be established; in vitro enzymatic and cell-based validation is therefore required.
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DOI: 10.3390/ph19091382
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