Search Results (2,135)

Background/Objectives: Niclosamide is an U.S. Food and Drug Administration (FDA)-approved antihelminthic drug with a long-established safety profile and demonstrated in vitro antiviral activity against Zika virus. Its evaluation for systemic indications has been limited by its poor oral bioavailability. This Phase I study assessed whether oral administration of the approved niclosamide formulation could achieve plasma concentrations comparable to those with reported antiviral activity. Methods: This single-center, open-label, randomized, two-period crossover Phase I study evaluated the safety, tolerability, and pharmacokinetics of oral niclosamide in healthy adult volunteers. Twelve participants received niclosamide 2 g once daily for three consecutive days under fed or fasted conditions, followed by crossover after a 14-day washout period. Plasma niclosamide concentrations were quantified using a validated Liquid Chromatography-Mass Spectrometry (LC–MS/MS) assay, and pharmacokinetic parameters were derived via non-compartmental analysis. Safety assessments included adverse event monitoring, clinical laboratory testing, vital signs, electrocardiograms, and physical examinations. Results: Nine participants per protocol completed the study. Niclosamide was safe and well tolerated under both fed and fasted conditions, with only mild to moderate, transient adverse events and no serious or severe events. Systemic exposure was markedly higher following fed administration, with mean maximum observed plasma concentration (C_max) and Area Under the Curve (AUC) values several-fold greater than those observed under fasted conditions. Under fed conditions, mean plasma niclosamide concentrations exceeded the reported in vitro Zika virus half-maximal inhibitory concentration (IC₅₀₎ (0.22 µM) for approximately 9 h post-dose on both Day 1 and Day 3. Fasted administration did not consistently achieve this exposure threshold. No unexpected accumulation was observed with repeated once-daily dosing. Conclusions: Oral niclosamide administered at the approved daily dose of 2 g is safe and well tolerated in healthy volunteers. Administration with food substantially enhances systemic exposure and transiently achieves plasma concentrations associated with in vitro antiviral activity against Zika virus. These findings support further development of optimized niclosamide formulations to achieve sustained systemic exposure for antiviral therapeutic applications. Full article

Background/Objectives: Tripterygium glycosides (TG) are used to treat inflammatory and autoimmune diseases, but their clinical application is limited by toxicity and the lack of process-responsive quality markers. This study examined whether roasting and dealkalization remodel the TG metabolite profile and alter the post-dose serum profile of circulating prototype constituents. Methods: Self-prepared TG, roasted TG (RTG), roasted–dealkalized TG (RDTG), and five marketed products were profiled by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Seven representative compounds were quantified by validated high-performance liquid chromatography (HPLC). Rat serum after oral administration was analyzed to compare circulating prototype constituents. Results: We characterized 243 constituents in material samples and 63 circulating prototype constituents in serum. Roasting primarily reshapes the profiles of diterpenoids and triterpenoids. Celastrol was not detected in the RTG and RDTG material samples, nor in the corresponding single-time-point serum profiles under the current analytical conditions. In contrast, wilforlide A exhibited an increase in material samples. Dealkalization preferentially reduced alkaloid-related constituents, including wilforine in material samples and tripterygiumine T in serum. Conclusions: Integrated material profiling, targeted quantification, and serum prototype analysis identified candidate process-responsive markers for processed TG preparations. Because the serum study was based on relative signal intensities rather than full pharmacokinetics, these markers require further pharmacokinetic and toxicological validation. Full article

Essential oils are multicomponent natural products with potential neurobehavioral activity, but integrated comparative studies remain limited. This study compared the essential oils of Satureja brevicalyx, Peperomia dolabriformis, and Rosmarinus officinalis in relation to their chemical profiles, predicted target interactions, preliminary acute oral safety, anxiolytic-like and antidepressant-like effects, antagonist-sensitive behavioral patterns, and exploratory serum biomarkers. Oils were characterized by GC-MS, and their constituents were screened by molecular docking against anxiety-, depression-, sleep-, and stress-related targets. Independent cohorts of male BALB/c mice received oral essential oils (25–100 mg/kg) and were assessed in anxiety-related, depression-related, and locomotor behavioral paradigms, including the elevated plus maze, light–dark box, marble burying, tail suspension, forced swim, and open field tests. Flumazenil and WAY-100635 were used to examine whether the behavioral responses were sensitive to γ-aminobutyric acid type A (GABA-A)/benzodiazepine- and serotonin 1A (5-HT1A)-related pharmacological modulation, respectively. In a preliminary 24-h acute oral toxicity screen, no mortality was observed up to 5000 mg/kg. The three oils produced anxiolytic-like and antidepressant-like effects without reducing spontaneous locomotor activity. Within its experimental block, S. brevicalyx showed the most consistent flumazenil-sensitive anxiolytic-like pattern and FDR-significant reductions in corticosterone and TNF-α, together with increased IL-4. P. dolabriformis showed a broader predicted multitarget docking profile and antagonist-sensitive behavioral attenuation compatible with mixed pathway participation. R. officinalis produced significant but more moderate behavioral effects. WAY-100635 partially attenuated the antidepressant-like effects of all three oils. These findings support differentiated but convergent functional neurobehavioral profiles among the oils. The docking, antagonist, and biomarker results should be interpreted as hypothesis-generating evidence of possible pathway involvement, supporting further validation in chronic stress models, receptor-specific assays, pharmacokinetic studies, and expanded safety evaluations. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Background/Objectives: Tirzepatide is a dual GIP and GLP-1 receptor agonist indicated for the treatment of type 2 diabetes and obesity. Oral delivery of tirzepatide is limited by poor gastrointestinal permeability, pH-dependent solubility, and manufacturing challenges associated with high-dose absorption enhancers. Methods: This study developed an immediate-release oral tirzepatide tablet using a Quality by Design (QbD) approach. Sodium caprate (C10) was selected as the absorption enhancer based on acid-neutralizing capacity, Caco-2 permeability enhancement, and preliminary rat pharmacokinetic screening. Quality target product profile, critical quality attributes, preliminary hazard analysis, and failure mode and effects analysis identified binder/disintegrant ratios as critical material attributes and hammer milling conditions as critical process parameters. Face-centered central composite designs and multiple-response optimization (MRO) were applied to optimize dissolution, flowability, and tablet mechanical integrity. Results: The optimized binder/disintegrant composition produced benchmark-comparable dissolution profiles against oral semaglutide tablets in pH 1.2, 4.0, and 6.8 media, with f₂ values exceeding 50 for both C10 300 mg and 500 mg formulations. The optimized process yielded tablets with low friability (0.58%) and acceptable flowability (Carr’s index, 24). In beagle dogs, the C10 300 mg formulation achieved higher systemic exposure than the C10 500 mg formulation, with a C_max of 46.49 ± 23.79 ng/mL and AUC_last of 1261.03 ± 690.44 h·ng/mL. Conclusion: These results support C10-mediated oral tirzepatide delivery and QbD-based optimization for oral peptide tablets. Full article

Diabetes mellitus (DM) is a highly prevalent metabolic disorder and a major public health concern. Pioglitazone, a widely used antidiabetic agent, exhibits limited therapeutic efficiency due to poor water solubility and suboptimal pharmacokinetic properties. Similarly, curcumin (Cur), a natural polyphenol with pleiotropic biological activities, is hindered by low oral bioavailability. In this study, chitosan-based nanocarriers were developed for the delivery of pioglitazone (CS-Pio NPs), curcumin (CS-Cur NPs), and their co-encapsulation (CS-Pio-Cur NPs), aiming to enhance their biological performance and therapeutic efficacy. The co-loaded nanosystem (CS-Pio-Cur NPs) demonstrated significantly enhanced antioxidant activity, as evidenced by DPPH (71.29 ± 0.09%), ABTS (86.08 ± 0.04%), and hydroxyl radical scavenging (87.08 ± 0.06%) assays, along with a strong reducing capacity (IC₅₀ = 25.39 ± 0.23 μg/mL). In a diabetic rat model, CS-Pio-Cur NPs significantly reduced blood glucose level and HbA1c (6.60 ± 0.83%), while also improving liver and kidney function parameters and lipid profile. These findings suggest that co-delivery of Pio and Cur via CS-based nanocarriers provides a combined therapeutic effect by simultaneously targeting hyperglycemia, oxidative stress, and associated metabolic dysfunctions. This nanosystem represents a promising approach for improving the management of DM and its complications. Full article

The search for effective alternatives or adjuncts to conventional anti-infective strategies in food animals has increased interest in plant-derived bioactive compounds. Matrine, a quinolizidine alkaloid derived from Sophora flavescens, has attracted considerable attention because of its broad bioactivities and potential veterinary relevance. Recent oral pharmacokinetic and intestinal-lumen PBPK studies in pigs have begun to emerge; however, currently available swine data remain largely confined to oral exposure-oriented experiments and do not permit direct route comparison or estimation of absolute oral bioavailability. In the present study, the plasma pharmacokinetics of matrine in pigs were evaluated after single-dose intravenous and oral administration. Twelve healthy piglets received matrine at 8 mg/kg body weight via either the intravenous or oral route, and plasma concentrations were quantified using a validated UPLC–MS/MS method. Pharmacokinetic parameters were estimated by non-compartmental analysis. Compared with intravenous administration, oral dosing produced lower observed exposure based on ${\mathrm{A}\mathrm{U}\mathrm{C}}_{0-t}$ and a lower peak plasma concentration, with ${\mathrm{A}\mathrm{U}\mathrm{C}}_{0-t}$ and ${\mathrm{C}}_{\max }$ values of 418.94 ± 75.52 h·ng/mL and 66.24 ± 8.44 ng/mL, respectively, versus 558.01 ± 59.57 h·ng/mL and 224.64 ± 20.94 ng/mL after intravenous administration. Oral administration was associated with a ${\mathrm{T}}_{\max }$ of 2.49 ± 0.02 h and a longer apparent terminal half-life and mean residence time than intravenous dosing. These findings provide pharmacokinetic evidence to support future route selection, dosing-regimen design, and PK/PD-based dose optimization of matrine in pigs. Full article

Redox homeostasis is the balance between oxidative processes and antioxidant defenses and is fundamental to cellular integrity. This review critically synthesizes current evidence on the phytochemical composition, redox-modulating mechanisms, and therapeutic bioactivities of Fagonia cretica L. (F. cretica), with the aim of evaluating its translational potential as a natural antioxidant and anticancer agent. F. cretica has emerged as a phytochemically rich candidate containing highly bioactive secondary metabolite for redox-targeted therapeutic applications. Its diverse secondary metabolite profile, including alkaloids, flavonoids, tannins, saponins, terpenoids, glycosides, and phenolic compounds, confers broad biological activity. Bioactive constituents, particularly kaempferol, catechin, quercetin, and arbutin, directly neutralize reactive oxygen species (ROS) and modulate inflammatory pathways through inhibition of COX-1, COX-2, and nitric oxide production. These compounds influence important major ROS-sensitive redox signaling pathways: activation of the Keap1/Nrf2/ARE axis to upregulate cytoprotective genes such as HO-1, NQO1, and GCL, suppression of the NF-κB pathway to attenuate pro-inflammatory cytokine transcription, including TNF-α, IL-1β, and IL-6, and interference with the MAPK-PI3K/Akt cascade to disrupt aberrant cancer cell survival and proliferation. Bioactive compound-rich extracts of F. cretica exhibit anticancer activity in MCF-7 breast cancer cells by inducing DNA damage, cell cycle arrest, and apoptotic signaling through the FOXO3a/p53 pathways. Similar effects have been reported in colorectal (HCT-116) and prostate (PC-3) cancer cells through DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation, oxidative stress induction, and ER-β activation. Moreover, these extracts demonstrate cytotoxic effects in HepG2 and Caco-2 intestinal cancer cells, often associated with topoisomerase inhibition and caspase activation. Despite encouraging preclinical evidence, systematic studies encompassing pharmacokinetic profiling, toxicological characterization, and human clinical trials remain essential to translate these findings into safe, evidence-based therapeutic applications. Full article

Petiveria alliacea L. (commonly known as “anamu,” “guiné,” “hierba de zorro,” and “tipi”) has been widely used in Mesoamerican traditional medicine to treat pain and inflammation. However, scientific evidence supporting its efficacy in diabetic neuropathy remains limited. This study evaluated the antinociceptive potential of a methanolic leaf extract of P. alliacea in a murine model of alloxan-induced diabetic neuropathy and investigated its possible mechanisms of action. Diabetic CD-1 mice were evaluated for mechanical allodynia and hyperalgesia using the Von Frey test and for tonic pain using the formalin test. Pharmacological antagonists were administered to assess the involvement of opioid, nitric oxide, serotonergic, and GABAergic pathways. Phytochemical profiling was performed by LC-ESI-MS/MS, and potential pharmacological and pharmacokinetic properties of the identified metabolites were predicted using in silico tools (PASS online, SwissTargetPrediction, SwissADME, and pkCSM). The methanolic extract significantly reduced mechanical allodynia and hyperalgesia in diabetic mice and attenuated nociceptive responses in both phases of the formalin test, showing an effect comparable to gabapentin. Antinociceptive activity was not altered by naloxone or L-NAME but was significantly attenuated by methiothepin and bicuculline, suggesting that serotonergic and GABAergic pathways contribute, at least in part, to the observed antinociceptive effects. LC-ESI-MS/MS analysis identified 38 metabolites, including flavonoids, alkaloids, and terpenes, with in silico predictions supporting their potential analgesic and anti-inflammatory activities. The methanolic leaf extract of P. alliacea exhibits significant antinociceptive activity in diabetic neuropathy, partially likely to involve serotonergic and GABAergic mechanisms, supporting its ethnomedicinal use and its potential as a source of novel analgesic agents. Full article

Natural products like the isoprenylated flavonoid Kuwanon G (KWG), isolated primarily from Morus alba, offer promising pleiotropic effects against multifactorial diseases, overcoming the limitations of conventional single-target synthetic drugs. This study aims to systematically review the pharmacological activities of KWG and evaluate its underlying molecular mechanisms. A comprehensive literature review was integrated with network pharmacology, protein–protein interaction (PPI) profiling, and KEGG/GO pathway enrichment analyses to identify shared targets across different pathologies. Experimental data demonstrate that KWG exhibits antimicrobial, anti-inflammatory, antidiabetic, neuroprotective, anti-obesity, and anticancer properties. Bioinformatics analyses revealed that KWG exerts these effects by modulating core targets (e.g., TNF, IL-6, SRC, RELA) and key signaling pathways, including NF-κB, PI3K/AKT/mTOR, and Toll-like receptors, which govern inflammation, oxidative stress, and metabolic regulation. In conclusion, KWG is a potent, multi-target compound with significant therapeutic potential for managing chronic and infectious diseases. However, future structure–activity relationship studies and clinical trials are required to address its pharmacokinetic limitations, such as low bioavailability, to facilitate its clinical translation. Full article

Lippia alba (Mill.) N.E. Br. ex Britton & P. Wilson is an aromatic medicinal plant widely used in traditional medicine for the management of digestive, inflammatory, and infectious disorders. The present study aimed to investigate the ethnobotanical relevance, chemical composition, antioxidant, antifungal, antibacterial, and molecular docking properties of L. alba essential oil (EOLA). Ethnobotanical information was collected through semi-structured interviews with herbal vendors. The essential oil was obtained by hydrodistillation and chemically characterized by GC–MS and GC–FID, leading to the identification of 27 volatile constituents. The chemical profile was dominated by oxygenated monoterpenes (83.83%), with (−)-carvone (63.79%) and dihydrocarvyl acetate (17.74%) as the major compounds, confirming a carvone chemotype. EOLA exhibited moderate antioxidant activity, with values of 24.1 mg TE/100 g and 34.5 mg TE/100 g in the DPPH and ABTS assays, respectively. Furthermore, the essential oil demonstrated significant concentration-dependent antifungal and antibacterial activities against Candida albicans and Staphylococcus aureus. At the highest concentration tested, the antimicrobial activity approached that of the reference drugs. In silico ADMET analysis predicted favorable pharmacokinetic and drug-likeness properties for the major volatile constituents. Molecular docking studies revealed relevant interactions between several compounds, particularly α-gurjunene, alloaromadendrene, trans-α-bisabolene, and (−)-β-bourbonene, and molecular targets associated with oxidative stress and microbial inhibition, providing mechanistic insights into the biological activities observed experimentally. Overall, these findings support the ethnopharmacological use of L. alba and highlight its essential oil as a promising natural source of bioactive compounds with antioxidant and antimicrobial potential for future phytopharmaceutical applications. Full article

Background: Hyperuricemia is an adverse effect frequently observed during favipiravir treatment. The time course, from uric acid elevation to recovery, and quantitative relationship between drug exposure and changes in serum uric acid levels remain insufficiently characterized. We investigated the pharmacodynamic mechanism of uric acid elevation and described its time course by population pharmacokinetic and pharmacodynamic modelling. Methods: Patients who received favipiravir for coronavirus disease 2019 or severe fever with thrombocytopenia syndrome were retrospectively evaluated. The pharmacokinetics of favipiravir were described by a one-compartment model with first-order absorption and elimination. Metabolite concentrations were predicted based on previously reported values. Changes in serum uric acid levels were described by a turnover model with zero-order production and first-order elimination. The drug effect was implemented as inhibition of the uric acid elimination process. Simulations based on the final model were performed for 10 consecutive days after the clinical regimen, with a 21-day follow-up. Results: The final model supported the inhibition of uric acid elimination by favipiravir and its metabolite. Regarding simulations, serum uric acid levels reached a median peak of 6.93 mg/dL at 6.7 days after treatment initiation and returned to pre-treatment levels within 4.0 days after treatment discontinuation. Conclusions: This combined population pharmacokinetic and pharmacodynamic turnover model quantified favipiravir-associated increases in serum uric acid levels and showed a transient profile with rapid recovery after drug discontinuation. These findings underscore the need for monitoring serum uric acid levels during favipiravir treatment, particularly in patients at a higher risk of gout Full article

This study aims identify plant-derived compounds that can inhibit glutathione peroxidase 4 (GPX4) enzyme and evaluate them through molecular docking, dynamics simulations, and ADMET analyses. The 3D structure of the GPX4 protein (PDB ID: 2OBI) was obtained from the Protein Data Bank. The plant-derived ligand library was compiled from the PubChem database and screened for compliance with Lipinski’s rules using ADMETLAB 2.0. Molecular docking simulations were performed using Autodock Vina. Molecular dynamics simulations of 100 nanoseconds were performed for the selected ligand–protein complexes using AMBER Tools and OpenMM software. The ADMET properties of the ligands were evaluated using the pKCSM web server. Compared to the reference inhibitor RSL3 (−7.2 kcal/mol), five plant compounds showed stronger binding affinity: withaferin A (−8.0 kcal/mol), mahanine (−7.9 kcal/mol), pseudobufarenogin (−7.8 kcal/mol), cucurbitacin I (−7.6 kcal/mol), and liquiritin (−7.5 kcal/mol). Molecular dynamics simulations showed that the complexes of withaferin A, mahanine, and liquiritin exhibited superior structural stability. ADMET analysis revealed that the compounds generally possess acceptable pharmacokinetic profiles but require some bioavailability optimization. The identified plant-derived compounds can be considered as potential therapeutic agents in cancer treatment by inducing ferroptosis via GPX4 inhibition. These findings provide an important basis for natural product-derived drug discovery studies. Full article

Gamma irradiation is one of the techniques widely authorized for the decontamination of dried herbs and spices. Its effect on the functional properties of essential oils, however, remains incompletely characterized. In this study, we examined the impact of gamma irradiation (at 5, 15, and 25 kGy) on the phytochemical composition, antimicrobial activity, antioxidant capacity, and insect-repellent activity of Cymbopogon citratus essential oil. The GC-MS analysis revealed that the citral-dominant chemotype remained stable across all irradiation doses, with geranial and neral constituting approximately 62–63% of the volatile profile. The antibacterial assays were done on five bacterial strains (Staphylococcus aureus, Bacillus subtilis, Streptococcus spp., Pseudomonas aeruginosa, and Klebsiella pneumoniae). Inhibition zones showed no statistically significant differences across irradiation doses (p ≥ 0.05), while MIC (75–100 µg/mL) and MBC (125–150 µg/mL) values remained constant across all doses. DPPH, ABTS, and FRAP antioxidant assays revealed no dose-dependent changes (DPPH IC₅₀: 688–703 µg/mL; ABTS IC₅₀: 18–22 µg/mL; FRAP: 505–517 µg/mL ascorbic-acid equivalents). The essential oil exhibited pronounced repellent activity (87–99%) against adult Tribolium confusum beetles at 0.125 µL/cm², persisting for 24 h and unaffected by irradiation. Molecular docking of the major constituents (geranial, neral, geraniol, and β-myrcene) against key target proteins (3N7H, 3NVY, 4URM, and 8BN6) provided predictive support consistent with the observed activities, indicating plausible molecular interactions rather than confirmed target engagement. In silico ADME and toxicity profiling indicated favorable predicted pharmacokinetic properties and no major in silico toxicity alerts for the four modeled constituents. Taken together, these findings indicate that, under the conditions tested, gamma irradiation at food-decontamination doses produced no major shifts in composition and no statistically detectable changes in the measured bioactivities of C. citratus essential oil. Full article

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative therapeutic strategies targeting bacterial virulence factors. This study employed an integrated in silico approach to identifying potential inhibitors of the iron-regulated surface determinant B Near-iron Transporter domain, a key protein involved in heme acquisition and pathogenicity. Virtual screening and molecular docking identified certain similarity-selected small molecules possessing strong binding affinities, with (4-(1-oxoisoindolin-2-yl)benzoic acid (TOP1) and (4-(2-oxochromen-3-yl)benzoic acid (TOP2) exhibiting the most favorable binding energies at −12.0 and −11.8 kcal/mol, respectively. Molecular dynamics simulations over 200 ns confirmed stable protein–ligand interactions that yielded reduced structural fluctuations in ligand-bound complexes when compared with the apo form. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis revealed that van der Waals interactions were the primary contributors to binding, with TOP1 showing a more favorable overall binding energy. Drug-likeness and pharmacokinetic predictions indicated compliance with Lipinski’s rule of five and moderate bioavailability, although limited intestinal absorption was observed. Toxicity predictions indicated that both compounds are non-mutagenic but may exhibit hepatotoxicity. Notably, TOP1 exhibited potential nephrotoxicity, cardiotoxicity, and carcinogenicity, whereas TOP2 demonstrated a more favorable safety profile. These findings highlight a trade-off between binding affinity and safety, suggesting that TOP2 emerged as a computationally prioritized candidate for future experimental validation. Because the present findings represent computational predictions only, further orthogonal computational analyses and experimental studies are required to confirm the proposed binding modes, biological activity, and therapeutic potential of the identified compounds. Full article