Search Results (848)

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains highly aggressive and continues to limit clinical treatment for substantial cancer-associated morbidity and mortality worldwide. Despite advances in therapeutic interventions the lack of effective molecularly targeted treatments continues to restrict clinical management beyond conventional chemotherapy and radiotherapy. Among these therapeutic targets the ribosomal S6 kinase 4 (RSK4) has gained considerable attention because of its critical involvement in ESCC progression, survival and proliferation, suggesting its potential as a potential target for anticancer drug development. Methods: A series of thiazole-clubbed pyrimidine linked hydrazone hybrids (1–14) were synthesized via 4-aminothiazole-5-carbohydrazide functionalized intermediates and fully characterized and evaluated for their inhibitory activity against RSK4. Results: Biological assessment demonstrated that the synthesized analogues exhibited remarkable potency, with IC₅₀ values between 15.32 ± 1.35 and 54.61 ± 2.17 nM compared with the reference inhibitor BI-D1870 (IC₅₀ = 33.16 ± 1.34 nM). Among the evaluated compounds, 2, 8, 9, 13 and 14 emerged as the most potent candidates and showed pronounced activity towards RSK4. For further insights into the molecular basis of their activity the lead candidates were subjected to computational investigations, such as molecular docking, molecular dynamics simulations, in silico ADMET and ProTox-3.0 characterization. The computational analyses provided structural and pharmacological insights into experimentally observed RSK4 inhibitory activity, like predicted interactions, stability dynamically and preliminary ADMET/toxicity characteristics. This study supports the need for further optimization and experimental validation of the identified RSK4 active lead candidates. Conclusions: These findings highlight the thiazole-clubbed pyrimidine-linked hydrazone scaffold as a potential chemotype for promising scaffolds targeting RSK4 lead discovery, and the identified candidates warrant further investigation into ESCC cellular models to establish anticancer efficacy and pathway-level activity. Full article

Background/Objectives: Cyclin-dependent kinase 2 (CDK2) is a key regulator of cell-cycle progression and a potential anticancer target. This study aimed to identify alkaloid-derived CDK2 ligands using an integrated computational workflow and to obtain preliminary evidence of their effects on cancer-cell viability. Methods: Molecular docking with mVina and fast pulling of ligand (FPL) simulations were benchmarked using 20 experimentally characterized CDK2 inhibitors. A library of 2692 PubChem-derived alkaloids was screened, followed by ADMET evaluation, 100 ns molecular dynamics simulations, and FPL-based relative-affinity re-ranking. The three prioritized compounds were evaluated in HepG2 and HGC-27 cells using an MTT assay after 48 h of exposure. Results: Docking and FPL showed correlations with experimental affinity data of R_Dock = 0.549 ± 0.180 and R_W = −0.676 ± 0.119, respectively. CID 636885, CID 46184320, and CID 101691758 were prioritized for detailed evaluation. All three compounds reduced cell viability, with lower IC₅₀ values observed in HepG2 cells than in HGC-27 cells. CID 101691758 exhibited the highest growth-inhibitory activity among the tested compounds, with IC₅₀ values of 15.37 ± 0.46 µg mL⁻¹ in HepG2 cells and 52.64 ± 1.33 µg mL⁻¹ in HGC-27 cells. Conclusions: The workflow identified three preliminary alkaloid hits, with CID 101691758 showing the most favorable combined computational and cell-viability profile. However, the MTT assay does not establish direct CDK2 inhibition or kinase selectivity. Biochemical CDK2 inhibition, target-engagement, and kinase-panel studies are therefore required. Full article

Background: Cordyceps militaris (C. militaris) is a medicinal mushroom recognized for its diverse pharmacological activities, largely attributed to its principal bioactive nucleosides, cordycepin and adenosine. Although accumulating evidence supports their neuroprotective potential, the molecular mechanisms underlying their effects against Alzheimer’s disease (AD) remain incompletely understood. This study investigated the neuroprotective effects of cordycepin and adenosine against amyloid-β (Aβ₄₂)-induced neurotoxicity and explored their potential molecular mechanisms using integrated experimental and computational approaches. Methods: SH-SY5Y neuroblastoma cells were pretreated with cordycepin (COR), adenosine (ADE), or donepezil (DNPZ) prior to Aβ₄₂ exposure, and cell viability was assessed using the MTT assay. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were evaluated in silico, followed by network pharmacology to identify potential therapeutic targets and enriched biological pathways. Molecular docking and molecular dynamics simulations were performed to elucidate the interactions of the compounds with selected Alzheimer’s disease-related proteins. Results: COR and ADE significantly attenuated Aβ₄₂-induced cytotoxicity and improved SH-SY5Y cell viability. Network pharmacology identified 84 shared molecular targets, including 9 AD-associated genes. Protein–protein interaction analysis revealed hub genes involved in signal transduction, epigenetic regulation, and purine metabolism, while Gene Ontology and KEGG enrichment analyses highlighted pathways associated with neuroactive ligand–receptor interaction, calcium signaling, and inflammatory regulation. ADMET analysis predicted favorable pharmacokinetic properties for both compounds, although cordycepin was predicted to be AMES-positive. Molecular docking and molecular dynamics simulations demonstrated stable interactions of COR and ADE with liver X receptors (LXRα and LXRβ), whereas donepezil exhibited stronger binding affinity toward β-secretase (BACE1). Conclusions: COR and ADE exert neuroprotective effects through coordinated modulation of multiple AD-related signaling pathways rather than a single molecular target. These findings provide mechanistic insights into the neuroprotective activities of C. militaris-derived nucleosides and support further investigation of their potential as multi-target therapeutic candidates for AD and other neurodegenerative disorders. Full article

The c-Myc oncoprotein is a central regulator of oncogenic transcriptional programs that remains challenging to inhibit directly, necessitating strategies that target c-Myc–associated protein complexes rather than the protein alone. This study conducted an in silico evaluation of the natural biphenolic lignan pinoresinol as a potential modulator of the c-Myc–TBP–TAF1 (TATA-binding protein (TBP)- Multiple direct interactions of TBP with the MYC oncoprotein) transcriptional complex (PDB ID: 6E16). Prior to molecular docking, the protein structure was subjected to energy minimization using the AMBER ff14SB force field to optimize conformational stability and structural reliability; ligand preparation and docking were performed with standard, widely used tools (e.g., AutoDock Vina v1.1.2; visualization and interface analyses in UCSF Chimera/ChimeraX and SeamDock). Molecular docking and binding-interface analyses identified reproducible interactions within defined pockets P₀, P₁, and P₂, with pocket P₀ exhibiting the highest Drug Score of 0.82. Binding affinities ranged from −5.0 to −7.1 kcal/mol, which are consistent with moderate docking scores typical for small natural ligands. Across multiple ligand poses, LYS327, LYS310, and ASP209 emerged as consistent interaction hotspots, with LYS327 showing the most frequent contacts. Furthermore, in silico ADMET analysis predicted a high probability of cytotoxic inactivity (0.98), suggesting a favorable safety profile compared to traditional agents like vincristine. These results support a protein–protein interface-oriented approach and position pinoresinol as a promising lead scaffold for disrupting c-Myc–associated transcriptional regulation. Full article

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections. Full article

Gyrinops vidalii (Thymelaeaceae), a critically endangered agarwood-producing species native to Thailand and Laos and remains phytochemically unexplored. In this study, the chemical constituents and biological activities of the ethyl acetate (EtOAc) fraction of methanol extract of G. vidalii leaves were investigated. Phytochemical analysis led the isolation of mangiferin (1), iriflophenone 3-C-β-D-glucoside (2), aquilarinenside E (3), iriflophenone 2-O-α-L-rhamnoside (4), 5,7,4′-trimethoxyflavone (5), blumenol A (6), loliolide (7), 4-hydroxybenzoic acid methyl ester (8), and 4-hydroxybenzoic acid (9). Compound 1 exhibited potent DPPH radical scavenging activity with an SC₅₀ value of 19.35 μM), whereas iriflophenone (3a), obtained by acid hydrolysis of 3, and 5 showed promising α-glucosidase inhibitory activity with IC₅₀ values 100.06 and 174.57 μM, respectively. Molecular docking demonstrated favorable binding of both compounds within the α-glucosidase active site through hydrogen bonding, aromatic, and hydrophobic interactions, with binding energies of −7.4 and −8.0 kcal/mol, respectively. Predicted ADMET properties further supported the drug-like potential of both compounds, indicating favorable aqueous solubility, high intestinal absorption, and no predicted hepatotoxicity, while differences were observed in their predicted blood–brain barrier permeability. This study represents the first phytochemical investigation of G. vidalii, provides scientific support for its traditional use, and expands the chemotaxonomic knowledge of the closely related genera Gyrinops and Aquilaria. Full article

Crinum amoenum Roxb. ex Ker Gawl. (C. amoenum) is traditionally used in Nepal, but its antidiabetic potential remains insufficiently validated. This study characterized the 80% (v/v) ethanol bulb extract of C. amoenum and evaluated its antioxidant, α-amylase inhibitory, hypoglycemic, molecular docking, molecular dynamics (MD) simulation, and ADMET profiles. The ethanolic bulb extract was evaluated through phytochemical screening, thin-layer chromatography, total phenolic content (TPC), total flavonoid content (TFC) estimation, LC-MS analysis, antioxidant assays, α-amylase inhibition assays, acute toxicity testing, and hypoglycemic/oral glucose tolerance test (OGTT) studies in Wistar rats. Lycorine, pratorinine, and palmatine were docked against α-amylase (PDB ID: 5U3A) and GLP-1R (PDB ID: 6GB1), followed by 200 ns MD simulations and ADMET prediction. Qualitative analysis of the extract was positive for flavonoids, phenolic compounds, tannins, saponins, alkaloids, and carbohydrates, and a positive Salkowski reaction indicated the presence of constituents occurring in glycosidic form. The TPC was 173.38 ± 1.22 mg GAE/g, and the TFC was 314.58 ± 0.09 mg QE/g. LC-MS tentatively annotated lycorine, pratorinine, and palmatine based on retention time, m/z values in positive-mode electrospray ionization, and comparison with previously reported spectral information. The extract showed DPPH scavenging activity (IC₅₀: 90.98 μg/mL) and strong α-amylase inhibition (IC₅₀: 49.31 μg/mL) compared with acarbose (IC₅₀: 51.51 μg/mL). No deaths were observed following oral administration at 5000 mg/kg to rats. The 500 mg/kg dose produced the greatest hypoglycemic response, reducing blood glucose by 35.78% at 120 min in non-diabetic Wistar rats and by 19.21% at 60 min in glucose-loaded rats. Among all the compounds tested, pratorinine demonstrated the highest docking affinity with α-amylase (−8.2 kcal/mol; ASP300) and GLP-1R (−7.0 kcal/mol; GLY132). MD simulation supported greater stability of the α-amylase complex, and ADMET prediction identified pratorinine as a comparatively favorable predicted lead candidate (LD₅₀: 1000 mg/kg; Class 4 toxicity category). Pratorinine was identified as the most promising in silico antidiabetic candidate from the C. amoenum extract, primarily due to stable α-amylase interactions and favorable ADMET properties. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects mainly peripheral joints because of inflammation of the synovial membrane. Current treatments, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, although effective, are associated with high costs and several adverse effects. In this context, natural products have emerged as promising alternatives because of their potential therapeutic effects and lower toxicity. The objective of this review was to identify and evaluate natural substances with potential applications in RA treatment on the basis of studies published between 2015 and 2020. A literature search was conducted in SciELO, PubMed, and Google Scholar using the keywords “rheumatoid arthritis”, “treatment”, “toxicity”, and “natural products”. Additionally, we applied in silico methods to predict pharmacokinetic and toxicological parameters using ADMET Predictor^® (Simulation Plus) and compared the results with those of commercial drugs such as diclofenac, ibuprofen, and naproxen. Target fishing (reverse docking) was also performed to identify possible molecular targets related to RA. Seven natural compounds were identified, mostly evaluated through in vivo studies. Among them, paeoniflorin, quercetin, resveratrol, and celastrol are in clinical phases and present potential as RA treatments. In silico analysis highlighted curcumin, tetramethylpyrazine, and resveratrol as the most promising candidates, with ADMET profiles comparable or superior to those of current NSAIDs. In conclusion, natural products represent viable alternatives for RA therapy. However, further studies are essential to better understand their safety, pharmacokinetics, and drug interactions to ensure their clinical applicability. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, highlighting the need for safe and effective therapeutic strategies targeting multiple oncogenic pathways. Cinnamon (Cinnamomum spp.) contains several bioactive phytochemicals with reported antioxidant and anticancer properties; however, their potential interactions with key cancer-associated signaling proteins have not been comprehensively investigated. In this study, an integrated computational and preliminary experimental approach was employed to evaluate four major cinnamon phytochemicals, namely e-cinnamaldehyde, eugenol, p-cymene, and cinnamic acid. Consensus molecular docking was performed using AutoDock Vina (v1.2.7), Smina (v2020.12.10), and GNINA (v1.3.3) against phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and mammalian target of rapamycin (mTOR). Docking analyses were complemented by protein-ligand interaction profiling, pharmacokinetic and toxicity prediction (ADMET), and a 100 ns molecular dynamics simulation with MM/GBSA binding free-energy analysis of the selected mTOR-p-cymene complex. In addition, the antioxidant activity and cytotoxic effects of a crude methanolic cinnamon bark extract were evaluated using in vitro antioxidant assays and MTT assays against HCT-116 and HT-29 colorectal cancer cell lines. Consensus docking predicted that all four phytochemicals were capable of interacting with the selected protein targets, although the predicted binding profiles varied among the compounds. Eugenol showed comparatively more favorable predicted interactions with PI3K, p-cymene produced the lowest predicted docking score for NF-κB, and cinnamic acid displayed a comparatively consistent predicted multitarget binding profile across PI3K, NF-κB, and mTOR. ADMET analysis suggested that all compounds satisfied major drug-likeness criteria and exhibited predicted oral bioavailability, although potential cytochrome P450 interactions and hepatotoxicity were predicted for some compounds. Molecular dynamics simulation indicated that the selected mTOR-p-cymene complex maintained a stable binding pose throughout the simulation, while MM/GBSA analysis yielded a modest binding free-energy estimate (ΔG_bind = −4.70 ± 8.20 kcal/mol), which should be interpreted cautiously because of the observed energetic variability. The crude methanolic cinnamon bark extract exhibited antioxidant activity and reduced the viability of HCT-116 and HT-29 colorectal cancer cells in a concentration-dependent manner. Collectively, these findings provide computational predictions of potential interactions between selected cinnamon-derived phytochemicals and cancer-associated signaling proteins and are consistent with the preliminary observation that the crude cinnamon extract exhibits antioxidant activity and cytotoxic effects in colorectal cancer cell lines. However, the computational analyses do not establish direct inhibition of the PI3K/NF-κB/mTOR signaling pathway, and the biological assays were performed using a crude extract rather than isolated phytochemicals. Therefore, further studies using purified compounds, biochemical target validation, pathway-specific cellular analyses, and in vivo models are required to determine whether the predicted protein-ligand interactions contribute to the observed biological activity. Full article

Background/Objectives: The development of multifunctional small molecules capable of simultaneously addressing cancer progression and antimicrobial resistance represents an important challenge in medicinal chemistry. This study aimed to design, synthesize, and biologically evaluate a series of novel morpholine-based nitrogen-rich heterocyclic hybrids as potential anticancer and antibacterial agents, supported by computational investigations. Methods: Twelve morpholine-derived nitrogen-enriched heterocyclic hybrids incorporating pyran, triazine, pyrimidinone, and sulfur-containing scaffolds were synthesized and fully characterized using IR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Their antiproliferative activities were evaluated against MCF-7 and HCT-116 cancer cell lines. The most active compounds were further investigated through kinase inhibition assays, cell cycle analysis, apoptosis, mitochondrial membrane potential, intracellular ROS determination, and apoptosis-related gene expression. Antibacterial, antibiofilm, antioxidant, and computational studies, including molecular docking, molecular dynamics simulations, MM-GBSA/MM-PBSA binding free-energy calculations, DFT calculations, and ADMET prediction, were also performed. Results: Compounds 3, 10, and 12 exhibited the highest antiproliferative activity, with compound 10 emerging as the lead candidate. It potently inhibited EGFR, PI3K, and mTOR, with IC₅₀ values of 0.086 ± 0.003, 0.107 ± 0.005, and 0.223 ± 0.008 μM, respectively. Mechanistic investigations revealed G₂/M arrest in MCF-7 cells and G₀/G₁ arrest in HCT-116 cells, accompanied by apoptosis rates of 32.66% and 37.12%; mitochondrial membrane depolarization; a 3.55-fold increase in intracellular ROS; upregulation of caspase-3, caspase-9, and Bax; and downregulation of Bcl-2, supporting activation of the intrinsic apoptotic pathway. Compound 10 also displayed the broadest antibacterial spectrum, surpassed ciprofloxacin against several tested isolates, exhibited MIC values of 5–20 μg/mL, achieved 42.80% inhibition of Pseudomonas aeruginosa biofilm formation, and showed the strongest antioxidant activity in DPPH and ABTS assays. Computational analyses supported the experimental findings by predicting stable interactions with EGFR and Staphylococcus aureus DNA gyrase, together with favorable MM-GBSA/MM-PBSA binding free energies of −23.44 and −24.99 ± 2.71 kcal/mol, respectively. Conclusions: The present findings identify compound 10 as a promising multifunctional lead with potent anticancer, antibacterial, antibiofilm, antioxidant, and multitarget kinase inhibitory activities. The combined biochemical, cellular, and computational findings support the proposed involvement of the EGFR/PI3K/mTOR signaling pathway in its antiproliferative activity and identify DNA gyrase as a potential antibacterial target. Nevertheless, the present study is limited to in vitro biological evaluation and computational investigations. Therefore, further in vivo efficacy studies, pharmacokinetic profiling, toxicity assessment, and experimental validation of the proposed molecular targets are warranted before considering preclinical development. Full article

Endophytic bacteria from medicinal plants are increasingly recognised as sources of antimicrobial metabolites. However, the endophytic bacterial community of Mitrephora heyneana remains poorly explored. In the present study, endophytic bacteria were isolated from the leaves of M. heyneana, collected from the Western Ghats of Tamil Nadu, India. Among seven isolates, the plant endophyte strain from leaf 6th strain (PEL6) was identified as Paenibacillus lactis through 16S rRNA gene sequencing. The ethyl acetate extract of PEL6 (EAE-PEL6) was subjected to gas chromatography–mass spectrometry (GC-MS) analysis, which putatively identified 32 metabolites based on GC-MS library matching, including pyrrolo [1,2-a] pyrazine-1,4-dione derivatives and triazole compounds as major constituents. The EAE-PEL6 demonstrated significant in vitro antibacterial activity against Staphylococcus aureus. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity), profiling predicted drug-likeness and pharmacokinetic properties of selected candidate compounds. Molecular docking suggested favourable binding of selected metabolites to S. aureus target proteins; however, these interactions require experimental validation. Density Functional Theory calculations indicated that CID 70504 had the lowest Highest Occupied Molecular Orbital (HOMO)–Lowest Unoccupied Molecular Orbital (LUMO) energy gap, reflecting higher electronic reactivity. Molecular electrostatic potential mapping further supported its enhanced binding propensity. Molecular dynamics simulations suggested structural stability, with Root Mean Square Deviation, Solvent Accessible Surface Area, radius of gyration, and hydrogen-bond analyses indicating stable interactions throughout the 100 ns trajectory. Overall, this study identifies P. lactis PEL6 as a promising endophytic source of anti-S. aureus metabolites and provides candidates for future purification, structural confirmation, and biological validation. Full article

Background: Serous ovarian cancer (SOC) is the most aggressive subtype of epithelial ovarian cancer, frequently diagnosed at advanced stages with poor prognosis and chemotherapy resistance. Checkpoint kinase 1 (CHEK1), a key regulator of the DNA damage response, is overexpressed in ovarian cancer, making it a promising therapeutic target. No study has systematically evaluated natural compounds as CHEK1 inhibitors in SOC through an integrative transcriptomic and computational framework. Methods: A meta-analysis of three GEO datasets (GSE27651, GSE36668, GSE54388; n = 83) was performed using ImaGEO. DEGs were identified at |log₂FC| ≥ 2 and FDR < 0.05. Pathway enrichment, PPI network analysis, virtual screening of 40 phytochemicals against CHEK1 (PDB: 9CE4), 100 ns MD simulations, and ADMET profiling were conducted using established bioinformatics and computational tools. Results: A total of 511 DEGs were identified, with significant dysregulation of apoptosis, DNA repair, and cell cycle pathways. CHEK1 emerged as the central hub gene. Baicalein exhibited the highest binding affinity (−9.334 kcal/mol), surpassing Prexasertib (−7.2 kcal/mol). MD simulations confirmed complex stability, and ADMET profiling demonstrated favorable drug-likeness with zero Lipinski violations. Conclusions: CHEK1 is established as a validated therapeutic target in SOC, and Baicalein is identified as a computationally superior natural lead compound, warranting experimental validation in ovarian cancer models. Full article

Staphylococcus aureus (S. aureus) remains a major global pathogen and a significant public health concern due to its antibiotic resistance. This has spurred the search for new treatments, resulting in the discovery of two promising targets: FtsZ and FabI. Naturally occurring compounds berberine and lipophilic acids are known to bind these enzymes, respectively. This study aims to improve berberine’s binding affinity for FtsZ and enhance its interaction with FabI by designing hybrid compounds that could serve as dual inhibitors, targeting both active and allosteric sites. Forty-eight hybrids, derived from berberine and lipophilic acids with 10 to 22 carbons, were modeled. Molecular docking against five S. aureus enzyme crystal structures identified six compounds with geranic acid chains (1s, 1t, 1u, 2s, 2t, 2u) that showed the strongest binding. Among these, 2s, 2t, and 1t showed the greatest affinity for FtsZ, while 2u, 1u, and 1s targeted FabI, with binding energies around −8.2 to −10.5 kcal/mol. QSAR models estimated MICs within known inhibitor ranges, implying potential effectiveness. Hydrophobic and flexible features correlated with stronger interactions and activity. ADMET analysis indicated low toxicity for these hybrids. Modifying berberine with lipophilic acids appears to be a promising approach for developing plant-based dual inhibitors against S. aureus. Full article

The rapid expansion of the global nutraceutical industry has heightened the urgency for rigorous yet efficient safety assessment of food-derived bioactives. Conventional toxicological methods, while indispensable, are often costly, time-consuming, and insufficient to keep pace with the rapid product innovation in this sector. In this context, in silico models for predicting Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET), alongside broader computational toxicology tools, are increasingly recognized as scalable and cost-effective strategies for early-stage safety evaluation of nutraceuticals. Techniques such as quantitative structure–activity relationship (QSAR) modeling, molecular docking, and physiologically based pharmacokinetic (PBPK) simulation enable early prioritization of candidate compounds, forecasting of potential enzyme- or receptor-mediated interactions, and prediction of bioactive metabolite profiles, prior to costly experimental or clinical evaluation. Yet, their application in the nutraceutical domain presents unique challenges. Food matrices are chemically complex, bioactive data remain sparse and unevenly curated, and long-term, low-dose effects are difficult to capture with existing computational frameworks. These limitations constrain predictive accuracy and raise questions about general applicability across diverse classes of compounds. Therefore, this review critically examines both the opportunities and limitations of computational safety assessment for nutraceuticals. It synthesizes representative case studies, evaluates current methodological limitations, and discusses the evolving regulatory landscape alongside emerging integrative frameworks such as New Approach Methodologies (NAMs) that may guide the future of nutraceutical safety assessment. Full article