Search Results (325)

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide, characterized by remarkable molecular heterogeneity and poor clinical outcomes. Despite advancements in diagnosis and treatment, the prognosis for HCC remains dismal, largely due to late-stage diagnosis and limited therapeutic efficacy. Therefore, there is a critical need to identify novel therapeutic targets and explore alternative strategies, such as drug repurposing, to improve patient outcomes. Methods: In this study, we employed network pharmacology, molecular docking, and molecular dynamics (MD) simulations to explore the potential therapeutic targets of Nirmatrelvir in HCC. Results: Nirmatrelvir targets were predicted through SwissTarget (101 targets), SuperPred (1111 targets), and Way2Drug (38 targets). Concurrently, HCC-associated genes (5726) were retrieved from DisGeNet. Cross-referencing the two datasets identified 29 overlapping proteins. A protein–protein interaction (PPI) network constructed from the overlapping proteins was analyzed using CytoHubba, identifying 10 hub genes, with HDAC1, HDAC3, and STAT3 achieving the highest degree scores. Molecular docking revealed a strong binding affinity of Nirmatrelvir to HDAC1 (docking score = −7.319 kcal/mol), HDAC3 (−6.026 kcal/mol), and STAT3 (−6.304 kcal/mol). Moreover, Nirmatrelvir displayed stable dynamic behavior in repeated 200 ns simulation analyses. Binding free energy calculations using MM/GBSA showed values of −23.692 kcal/mol for the HDAC1–Nirmatrelvir complex, −33.360 kcal/mol for HDAC3, and −21.167 kcal/mol for STAT3. MM/PBSA analysis yielded −17.987 kcal/mol for HDAC1, −27.767 kcal/mol for HDAC3, and −16.986 kcal/mol for STAT3. Conclusions: The findings demonstrate Nirmatrelvir’s strong binding affinity towards HDAC3, underscoring its potential for future drug development. Collectively, the data provide computational evidence for repurposing Nirmatrelvir as a multi-target inhibitor in HCC therapy, warranting in vitro and in vivo studies to confirm its clinical efficacy and safety and elucidate its mechanisms of action in HCC. Full article

Background/Objectives: Moschus (musk) has long been used in traditional Tibetan medicine to prevent and treat epidemic febrile illnesses. However, its antiviral mechanisms remain poorly understood. Given the urgent need for effective treatments against viral respiratory tract infections (VRTIs), this study aimed to systematically investigate the molecular targets and pharmacological pathways through which Moschus may exert therapeutic effects. Methods: Based on the identification of bioactive compounds with favorable pharmacokinetics, we applied integrated network pharmacology and multi-omics analyses to systematically identify key therapeutic targets involved in VRTIs. Gene Set Enrichment Analysis (GSEA) and immune infiltration further revealed strong associations with multiple immune cell subsets, reflecting their pivotal roles in immunomodulatory mechanisms during viral infections. Molecular docking confirmed the strong binding affinities between Moschus compounds and these key targets. Results: Notably, testosterone exhibited the strongest and most consistent binding across key targets, suggesting its potential as a pivotal bioactive compound. Importantly, the antiviral effects of Moschus may be mediated in part by the downregulation of the key genes MCL1, MAPK3, and CDK2, which are involved in the regulation of viral replication, apoptosis, and host immune responses. Conclusions: This study provides a comprehensive mechanistic framework supporting the multi-target antiviral potential of Moschus, offering a scientific basis for its further development as a therapeutic agent against VRTIs. Full article

Background: The metabolic dysfunction-associated steatotic liver disease (MASLD) represents an escalating global health concern, with effective treatments still lacking. Given its complex pathogenesis, multi-targeted strategies are highly desirable. Methods: This study reports the isolation of four flavone C-glycosides (FCGs) from Dianthus superbus L. and explores their potential in treating MASLD. The bioactivity and underlying mechanisms of FCGs were systematically evaluated by integrating network pharmacology, molecular docking, and zebrafish model validation. Results: Network pharmacology analysis revealed that FCGs may modulate multiple MASLD-related pathways, including lipid metabolism, insulin signaling, inflammation, and apoptosis. Molecular docking further confirmed strong binding affinities between FCGs and key protein targets involved in these pathways. In the zebrafish model of MASLD induced by egg yolk powder, FCGs administration markedly attenuated obesity, hepatic lipid accumulation, and liver tissue damage. Furthermore, FCGs improved lipid metabolism and restored locomotor function. Molecular analyses confirmed that FCGs upregulated PPARγ expression to promote lipid metabolism, restored insulin signaling by enhancing INSR, PI3K, and AKT expression, and suppressed inflammation by downregulating TNF, IL-6 and NF-κB. Additionally, FCGs inhibited hepatocyte apoptosis by elevating the BCL-2/BAX ratio. Conclusions: These findings highlight the multi-pathway regulatory effects of FCGs in MASLD, underscoring its potential as a novel therapeutic candidate for further preclinical development. Full article

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

This study aimed to investigate the underlying mechanisms by which dandelion extract inhibits the proliferation of breast cancer MDA-MB-231 cells. Dandelion root and leaf extracts were prepared using a heat reflux method and subjected to solvent gradient extraction to obtain fractions with different polarities. MTT assays revealed that the ethyl acetate fraction exhibited the strongest inhibitory effect on cell proliferation. LC-MS analysis identified 12 potential active compounds, including sesquiterpenes such as Isoalantolactone and Artemisinin, which showed significantly lower toxicity toward normal mammary epithelial MCF-10A cells compared to tumor cells (p < 0.01). Mechanistic studies demonstrated that the extract induced apoptosis in a dose-dependent manner, with an apoptosis rate as high as 85.04%, and significantly arrested the cell cycle at the S and G2/M phases. Label-free quantitative proteomics identified 137 differentially expressed proteins (|FC| > 2, p < 0.05). GO enrichment analysis indicated that these proteins were mainly involved in cell cycle regulation and apoptosis. KEGG pathway analysis revealed that the antitumor effects were primarily mediated through the regulation of PI3K-Akt (hsa04151), JAK-STAT (hsa04630), and PPAR (hsa03320) signaling pathways. Moreover, differential proteins such as PI3K, AKT1S1, SIRT6, JAK1, SCD, STAT3, CASP8, STAT2, STAT6, and PAK1 showed strong correlation with the core components of the EA-2 fraction of dandelion. Molecular docking results demonstrated that these active compounds exhibited strong binding affinities with key target proteins such as PI3K and JAK1 (binding energy < −5.0 kcal/mol). This study elucidates the multi-target, multi-pathway synergistic mechanisms by which dandelion extract inhibits breast cancer, providing a theoretical basis for the development of novel antitumor agents. Full article

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics. Materials and Methods: The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses. Results: GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins. Conclusions: The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes. Full article

Cancer remains one of the most formidable challenges to human health; hence, developing effective treatments is critical for saving lives. An important strategy involves reactivating tumor suppressor genes, particularly p53, by targeting their negative regulator MDM2, which is essential in promoting cell cycle arrest and apoptosis. Leveraging a drug repurposing approach, we screened over 24,000 clinically tested molecules to identify new MDM2 inhibitors. A key innovation of this work is the development and application of a selective cleaning algorithm that systematically filters assay data to mitigate noise and inconsistencies inherent in large-scale bioactivity datasets. This approach significantly improved the predictive accuracy of our machine learning model for pIC₅₀ values, reducing RMSE by 21.6% and achieving state-of-the-art performance (R² = 0.87)—a substantial improvement over standard data preprocessing pipelines. The optimized model was integrated with structure-based virtual screening via molecular docking to prioritize repurposing candidate compounds. We identified two clinical CB1 antagonists, MePPEP and otenabant, and the statin drug atorvastatin as promising repurposing candidates based on their high predicted potency and binding affinity toward MDM2. Interactions with the related proteins MDM4 and BCL2 suggest these compounds may enhance p53 restoration through multi-target mechanisms. Quantum mechanical (ONIOM) optimizations and molecular dynamics simulations confirmed the stability and favorable interaction profiles of the selected protein–ligand complexes, resembling that of navtemadlin, a known MDM2 inhibitor. This multiscale, accuracy-boosted workflow introduces a novel data-curation strategy that substantially enhances AI model performance and enables efficient drug repurposing against challenging cancer targets. Full article

Lobelia nummularia Lam. is a traditional medicinal herb of which the anticancer mechanisms remain largely unexplored. Here, we demonstrated that its ethanolic extract (LNE) exerts potent anti-breast cancer activity by inducing ROS-dependent mitochondrial apoptosis in MDA-MB-231 cells, a mechanism confirmed via rescue experiments with the antioxidant N-acetylcysteine (NAC). This pro-apoptotic program is driven by a dual mechanism: potent suppression of the pro-survival EGFR/PI3K/AKT signaling pathway and simultaneous activation of the TP53-mediated apoptotic cascade, culminating in the cleavage of executor caspase-3. Phytochemical analysis identified numerous flavonoids, and quantitative HPLC confirmed that key bioactive compounds, including luteolin and apigenin, are substantially present in the extract. These mechanisms translated to significant in vivo efficacy, where LNE administration suppressed primary tumor growth and lung metastasis in a 4T1 orthotopic model in BALB/c mice. Furthermore, a validated molecular docking protocol provided a plausible structural basis for these multi-target interactions. Collectively, this study provides a comprehensive, multi-layered validation of LNE’s therapeutic potential, establishing it as a mechanistically well-defined candidate for natural product-based anticancer drug discovery. Full article

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation. Full article

Plant secondary metabolites possess significant antioxidant and anti-inflammatory properties, but their complex polypharmacological mechanisms remain poorly understood. Network pharmacology has emerged as a powerful systems-level approach for investigating multi-target interactions of natural products. This review systematically analyzes network pharmacology applications in elucidating the antioxidant and anti-inflammatory mechanisms of plant metabolites, evaluating concordance between computational predictions and experimental validation. A comprehensive literature search was conducted across major databases (2015–2025), focusing on network pharmacology studies with experimental validation. Analysis revealed remarkable convergence toward common molecular mechanisms, despite diverse chemical structures. For antioxidant activities, the Nrf2/KEAP1/ARE pathway emerged as the most frequently validated mechanism, along with PI3K/AKT, MAPK, and NF-κB signaling. Anti-inflammatory mechanisms consistently involved NF-κB, MAPK, and PI3K/AKT pathways. Key targets, including AKT1, TNF-α, COX-2, NFKB1, and RELA, were repeatedly identified. Flavonoids, phenolic acids, and terpenoids dominated as bioactive compounds. Molecular docking studies supported predicted interactions, with experimental validation showing good concordance for pathway modulation and cytokine regulation. Network pharmacology provides a valuable framework for investigating the complex bioactivities of plant metabolites. The convergence toward common regulatory hubs suggests that natural compounds achieve protective effects by modulating central nodes that integrate redox balance and inflammatory responses. Despite limitations, including database dependency, integrating network pharmacology with experimental validation accelerates mechanistic understanding in natural-product drug discovery. Full article

This study evaluated the in vitro anti-inflammatory activity of serotonin derivatives from safflower seed powder and elucidated their mechanism against ulcerative colitis using network pharmacology. Compounds were extracted and purified via silica gel column chromatography, Sephadex LH-20 and semi-preparative HPLC. Structural characterization employed NMR and UPLC-Q-TOF-MS/MS with literature comparisons. Anti-inflammatory efficacy was assessed in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Network pharmacology predicted targets, molecular docking analyzed binding interactions and molecular dynamics simulations assessed complex stability. Eleven serotonin derivatives were isolated; N-trans-Feruloyl-3,5-dihydroxyindolin-2-one (1) and Bufoserotonin A (2) were identified in safflower seed meal for the first time. Compounds 1, 3–7 and 10 significantly reduced inflammatory factors, with N-feruloyl serotonin (4, FS) showing the strongest activity. Mechanistic studies revealed FS targets key molecules (STAT3, EGFR, ESR1, PTGS2, NF-κB1, and JUN), modulating PI3K-Akt, MAPK and cancer-related pathways. Molecular dynamics simulations confirmed FS-EGFR complex stability. Thus, two novel derivatives were isolated and FS demonstrated significant anti-inflammatory and potential anti-ulcerative colitis effects through multi-target, multi-pathway synergy, providing a foundation for developing safflower seed meal therapeutics. Full article

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC₅₀ of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article

Background/Objectives: Human carbonic anhydrases (hCAs) are metalloenzymes involved in essential physiological processes, and their selective inhibition holds therapeutic potential across a wide range of disorders. However, the high degree of structural similarity among isoforms poses a significant challenge for the design of selective inhibitors. In this work, we present a machine learning (ML)-based platform for the isoform-specific prediction and profiling of small molecules targeting hCA I, II, IX, and XII. Methods: By integrating four molecular representations with four ML algorithms, we built 64 classification models, each extensively optimized and validated. The best-performing models for each isoform were applied in a virtual screening campaign for ~2 million compounds. Results: Following a multi-step refinement process, 12 candidates were identified, purchased, and experimentally tested. Several compounds showed potent inhibitory activity in the nanomolar to submicromolar range, with selectivity profiles across the isoforms. To gain mechanistic insights, SHAP-based feature importance analysis and molecular docking supported by molecular dynamics simulations were employed, highlighting the structural determinants of the predicted activity. Conclusions: This study demonstrates the effectiveness of integrating ML, cheminformatics, and experimental validation to accelerate the discovery of selective carbonic anhydrase inhibitors and provides a generalizable framework for activity profiling across enzyme isoforms. Full article

Background and aim: The COVID-19 pandemic, caused by SARS-CoV-2, remains a global health crisis despite vaccination efforts, necessitating novel therapeutic strategies. Natural compounds from Syzygium aromaticum (clove), such as eugenol and β-caryophyllene, exhibit antiviral and anti-inflammatory properties, while host genetic factors, including miR-21 rs1292037 polymorphism, may influence disease susceptibility and severity. This study investigates the dual approach of targeting SARS-CoV-2 via Syzygium aromaticum phytoconstituents while assessing the role of miR-21 rs1292037 in COVID-19 pathogenesis. Methods: Firstly, molecular docking and molecular dynamics simulations were employed to assess the binding affinities of eugenol and caryophyllene against seven key SARS-CoV-2 proteins—including Spike-RBD, 3CLpro, and RdRp—using SwissDock (AutoDock Vina) and the Desmond software package, respectively. Secondly, GC-MS was used to characterize the composition of clove extract. Thirdly, pharmacokinetic profiles were predicted using in silico models. Finally, miR-21 rs1292037 genotyping was performed in 100 COVID-19 patients and 100 controls, with cytokine and coagulation markers analyzed. Results: Docking revealed strong binding of eugenol to viral Envelope Protein (−5.267 kcal/mol) and caryophyllene to RdRp (−6.200 kcal/mol). ADMET profiling indicated favorable absorption and low toxicity. Molecular dynamics simulations confirmed stable binding of methyl eugenol and caryophyllene to SARS-CoV-2 proteins, with caryophyllene–7Z4S showing the highest structural stability, highlighting its strong antiviral potential. Genotyping identified the TC genotype as prevalent in patients (52%), correlating with elevated IL-6 and D-dimer levels (p ≤ 0.01), suggesting a hyperinflammatory phenotype. Males exhibited higher ferritin and D-dimer (p < 0.0001), underscoring sex-based disparities. Conclusion: The bioactive constituents of Syzygium aromaticum exhibit strong potential as multi-target antivirals, with molecular simulations highlighting caryophyllene’s particularly stable interaction with the 7Z4S protein. Methyl eugenol also maintained consistent binding across several SARS-CoV-2 targets. Additionally, the miR-21 rs1292037 polymorphism may influence COVID-19 severity through its role in inflammatory regulation. Together, these results support the combined application of phytochemicals and genetic insights in antiviral research, pending further clinical verification. Full article