In silico evaluation of jujube and olive leaves bioactive compounds for potential sleep-modulating effects

According to WHO, 16–25% of individuals worldwide experience sleep disorders, and in Indonesia around 10% of adults are affected. Long-term use of conventional insomnia medications can cause dependence, tolerance, and side effects, prompting interest in safer natural alternatives. Jujube leaves ( Ziziphus jujube ) and Olive leaves ( Olea europaea) have traditionally been used for relaxation and insomnia relief, but their molecular mechanisms remain unclear. This study aimed to evaluate the potential of their bioactive compounds in improving sleep quality through in silico approaches. Compounds were collected from literature, herb-related protein targets were obtained from public databases, biological activities were predicted using the PASS database, and pharmacokinetic properties were assessed via SwissADME. Protein–protein interaction networks were constructed using STRING and STITCH, hub genes were identified with Cytoscape, and Gene Ontology enrichment was performed using BiNGO. Three main active compounds and 25 therapeutic targets were identified. Key targets such as ABAT, GAD1, MTNR1A, MTNR1B, ASMT, and AANAT were strongly linked to GABA signaling, melatonin pathways, and neurotransmitter regulation, all essential for sleep improvement, while PTGS2 was associated with stress and inflammatory responses. Quercetin, Gallic Acid, and Apigenin showed strong potential to enhance sleep quality by modulating GABA levels, reducing histamine release, and providing anti-inflammatory effects. Network analysis revealed interactions between these compounds and proteins involved in GABA and melatonin metabolism. Overall, the findings indicate that jujube and olive leaves exert multi-compound, multi-target, multi-pathway effects that regulate inflammation, stress responses, neurotransmission, and sleep-related biochemical processes, supporting their potential as natural therapeutic agents for sleep disorders. • A large number of studies have explored the herbs, can be utilized not only to make food for human use but also to treat illnesses and offer medical care including for improving sleep quality. • The mechanism of sleep disorders has been extensively studied in neuroendocrine pathology and is mainly thought to be the problem of neurostransmitter in the brain, which are mostly produced in the hypothalamus, includes gamma-aminobutyric acid (GABA), melatonin (MT), 5-hydroxytryptamine (5-HT), acetyl choline (ACH), dopamine (DA), norepinephrine (NE), glutamic acid (Glu), histamine [19] etc. In addition, melatonin are mostly produced in the hypothalamus, determines whether a person is awake or asleep. It mainly includes gamma-aminobutyric acid (GABA), melatonin (MT), 5-hydroxytryptamine (5-HT), acetyl choline (ACH), dopamine (DA), norepinephrine (NE), glutamic acid (Glu), histamine, etc. In addition, the hypothalamic-pituitary-adrenal (HPA) axis are also involved in sleep-wake regulation system. • Insilico study will evaluate the potential of bioactive compounds from jujube leaves ( Ziziphus jujube ) and olive leaves ( Olea europaea ) in improving sleep quality through their bioactive compound that contain of phytomelatonin that can affect the sleep process. The study was conducted using the structure-activity relationship prediction (SAR) method, ADME analysis, and toxicity prediction to identify compounds with potential as inhibitors of GABA aminotransferase, anti-inflammatory, and antioxidant. • The results showed that three main compounds, namely Quercetin, Gallic Acid, and Apigenin, had high potential to improve sleep quality through mechanisms that increase GABA levels, inhibit histamine release, and anti-inflammatory activity. Further analysis by network analysis indicates the interaction of this compound with proteins associated with GABA and melatonin metabolism. The implications of this study show that Jujube and Olive leaves have the potential as natural ingredients in the treatment of sleep disorders.