Discovery of natural orexin 2 receptor antagonists from Valeriana species: A potential approach for insomnia treatment.

The orexinergic system, comprising orexin-A and orexin-B neuropeptides that bind to OX1R and OX2R receptors, plays a critical role in regulating sleep-wake cycles, appetite, and alertness. OX2R is particularly important for promoting arousal and non-rapid eye movement (NREM) sleep and has been linked to sleep disorders such as insomnia and narcolepsy. Although OX2R antagonists like suvorexant have shown therapeutic promise, they are often associated with side effects including cognitive impairment and dependence, highlighting the need for safer alternatives. This study employed an in-silico approach to identify natural OX2R antagonists from Valeriana species. Phytochemicals were screened based on molecular docking and favourable ADME/T profiles. Molecular dynamics (MD) simulations and post-MD analysis confirmed stable binding of hesperidine and valerosidate to OX2R. Principal component analysis (PCA) revealed minimal conformational variability while gibbs free energy landscape (FEL) analysis and MM-PBSA binding free energy calculations further supported the strong binding of hesperidine and valerosidate to OX2R, comparable to suvorexant. These findings support hesperidine and valerosidate as promising, naturally derived OX2R antagonists, and warrant further invitro and invivo investigations for potential therapeutic application in insomnia treatment.