Birth defects research · 2026
Computational Studies of Satureja hortensis Phytochemicals as Inhibitors of AP-1 (FOS/JUN) Activation in Valproic Acid Teratogenicity.
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Nagarakere Shankara Vindya, Ahmed Syed Sagheer, Doddla Raghunathanaidu Bharathi
Аннотация
BACKGROUND: Valproic acid (VPA) is a widely used antiepileptic drug and known teratogen that induces developmental defects in part via aberrant activation of the AP-1 (c-Fos/c-Jun) transcription factor pathway. We investigated whether phytochemicals from Satureja hortensis L. (summer savory) can modulate this pathway.
METHODS: In this study, we employed structure-based computational methods to screen phytoconstituents of S. hortensis against the AP-1 (Fos/Jun) transcription factor.
RESULTS: Molecular docking predicted that the top ligands, cedrelanol and allo-aromadendrene, bound the DNA-bound AP-1 complex (1FOS) with affinities of -7.7 kcal/mol each, exceeding the -7.3 kcal/mol affinity of the reference inhibitor SR11302. Subsequent 100-ns molecular dynamics simulation of the cedrelanol-1FOS complex confirmed stable binding the protein backbone RMSD remained between 0.8-1.2 Å and the ligand RMSD stayed below 1.3 Å throughout the trajectory. MM/GBSA binding free energy analysis further indicated a highly favorable ΔG_binding of -75.04 kcal/mol for the cedrelanol-1FOS complex.
CONCLUSION: These integrated results highlight cedrelanol as a potent AP-1 modulator, providing a molecular basis for exploring S. hortensis terpenoids to mitigate VPA-induced teratogenic AP-1 hyperactivation. These findings suggest that S. hortensis phytochemicals as plausible inhibitors of AP-1, with potential implications for developing plant-derived agents to mitigate VPA teratogenicity.
METHODS: In this study, we employed structure-based computational methods to screen phytoconstituents of S. hortensis against the AP-1 (Fos/Jun) transcription factor.
RESULTS: Molecular docking predicted that the top ligands, cedrelanol and allo-aromadendrene, bound the DNA-bound AP-1 complex (1FOS) with affinities of -7.7 kcal/mol each, exceeding the -7.3 kcal/mol affinity of the reference inhibitor SR11302. Subsequent 100-ns molecular dynamics simulation of the cedrelanol-1FOS complex confirmed stable binding the protein backbone RMSD remained between 0.8-1.2 Å and the ligand RMSD stayed below 1.3 Å throughout the trajectory. MM/GBSA binding free energy analysis further indicated a highly favorable ΔG_binding of -75.04 kcal/mol for the cedrelanol-1FOS complex.
CONCLUSION: These integrated results highlight cedrelanol as a potent AP-1 modulator, providing a molecular basis for exploring S. hortensis terpenoids to mitigate VPA-induced teratogenic AP-1 hyperactivation. These findings suggest that S. hortensis phytochemicals as plausible inhibitors of AP-1, with potential implications for developing plant-derived agents to mitigate VPA teratogenicity.