IntroductionBreast cancer is the second most diagnosed cancer worldwide, with WEE1 kinase recognized as a key regulator of tumor progression. Natural products, particularly plant-derived metabolites, offer promising scaffolds for the development of novel WEE1 inhibitors. Materials and MethodsEthanol extracts of Ampelocissus thyrsiflora (Blume) Planch, a North Sumatran endemic plant, were obtained via maceration and subjected to phytochemical screening, PASS prediction, and Lipinski’s Rule of Five evaluation. Molecular docking and 100 ns molecular dynamics (MD) simulations were performed to investigate ligand–protein interactions. Cytotoxicity was assessed using the MTT assay on MCF-7 breast cancer cells. ResultsPhytochemical analysis confirmed the presence of alkaloids, flavonoids, saponins, tannins, glycosides, and steroids. Fourteen compounds exhibited strong predicted biological activity, and thirteen fulfilled drug-likeness criteria. Based on binding affinity and interactions with key WEE1 residues, four compounds were selected for MD simulations. Three demonstrated favorable MM-PBSA binding energies and stable interactions with critical residues. The ethanol extract showed an IC50 of 2011.25 ± 42.71 µg/mL against MCF-7 cells. DiscussionThe computational results highlight the potential of A. thyrsiflora metabolites as multi-target inhibitors of WEE1 kinase. Although the obtained IC50 value is comparatively high, the result provides an important preliminary basis for subsequent investigations and potential optimization of its active constituents. ConclusionAlthough the ethanol extract of A. thyrsiflora exhibited a high in vitro IC50, the in silico results provide a strong rationale for further exploration of its metabolites as potential WEE1-targeted anticancer agents.
Introduction Cancer remains a leading global health challenge, with drug resistance, toxicity, and economic burden limiting the effectiveness of existing therapies. Matrix metalloproteinase-2 (MMP-2), a key gelatinase involved in extracellular matrix (ECM) degradation, plays a crucial role in cancer metastasis and represents a promising target for anticancer drug development. Materials and Methods This study focuses on designing novel MMP-2 inhibitors by employing a comprehensive 2D-Quantitative Structure-Activity Relationship (2D-QSAR) analysis of 71 pyrrolidine derivatives with reported anticancer activity. Docking studies using Autodock Vina software were performed, followed by ADMET analysis using the SwissADME server. Results A robust QSAR model was developed using multiple linear regression (MLR) analysis, demonstrating high reliability, statistical significance, and predictive accuracy ( r = 0.918, r 2 cv = 0.842, r 2 pred = 0.798). Discussion Based on QSAR insights, new pyrrolidine derivatives were designed, and their anticancer potential was evaluated through molecular docking studies against MMP-2 (PDB ID: 1HOV). ADMET analysis revealed favorable pharmacokinetic and toxicity profiles for all of the designed compounds. Docking studies showed strong binding affinities, highlighting the potential of these compounds as selective and potent MMP-2 inhibitors. Conclusion An integrative approach using QSAR modeling, molecular docking, and ADMET analysis provides a valuable framework for designing effective anticancer agents targeting MMP-2.
Introduction Dobutamine, a well-established β 1 -adrenergic agonist, has demonstrated anti-proliferative effects against several cancer cell types. However, the molecular mechanism underlying this activity has remained elusive. Collective evidence from the literature indicates that dobutamine-sensitive cancers-including osteosarcoma, gastric adenocarcinoma, and multiple myeloma-frequently overexpress Rho-associated protein kinase 2 (ROCK2). To evaluate the hypothesis that dobutamine can act as a ROCK2 inhibitor. Methods A comprehensive approach was employed, including enzymatic assays, cell-based proliferation studies in cell lines with differential ROCK2 expression, and computational molecular docking analyses. Results Enzyme assays demonstrated that dobutamine inhibits ROCK2 with a half-maximal inhibitory concentration (IC 50 ) of 7.1 µM. In cellular assays, dobutamine induced a ROCK2 expression-dependent anti-proliferative effect, showing approximately fourfold greater potency against the high-ROCK2-expressing HepG2 cell line compared to the low-ROCK2-expressing T-47D cell line. Furthermore, molecular docking studies revealed a plausible ATP-competitive binding mode of dobutamine within the ROCK2 kinase domain, stabilized by key hydrogen bonding, hydrophobic interactions, and π-cation interactions. Discussion Our findings provide the first direct evidence that dobutamine inhibits ROCK2 enzymatic activity, as demonstrated by both enzyme-based and cell-based assays. Moreover, our results validate dobutamine's chemical scaffold as a promising starting point for the structure-based design of more potent and selective ROCK2-targeted anticancer agents. Notably, we identified two major thermodynamic limitations contributing to its suboptimal binding affinity: a high entropic penalty and an enthalpic penalty associated with desolvation. Accordingly, clear medicinal chemistry optimization strategies can be employed to overcome these issues. Conclusion This study establishes a novel mechanistic link between dobutamine and ROCK2 inhibition, providing a strong rationale for its therapeutic repurposing.
Introduction Cardiovascular Diseases (CVDs) continue to be the leading cause of death globally, which highlights the need to evaluate nutraceuticals like Aged Garlic Extract (AGE) for risk factor management. This systematic review and meta-analysis compiles the data on how AGE affects blood pressure, lipid profiles, inflammation, and glycaemic control in adults at risk for CVD. Methods PRISMA guidelines were followed when searching databases (PubMed, Cochrane CENTRAL, Google Scholar) for randomized, double-blind, placebo-controlled trials from the beginning to May 2025. Research that was observational or crossover was not accepted. Standardised Mean Differences (SMDs) with 95% Confidence Intervals (CIs) were calculated using random-effects models, and the risk of bias was assessed using Cochrane tools. Results Systolic (-1.71 mmHg, p = 0.54) and diastolic (-0.77 mmHg, p = 0.44) blood pressure decreased non-significantly in ten trials (n = 625), with dose-dependent trends ( e.g ., -1.25 mmHg SBP at ≤ 1200 mg/day). Triglycerides trended lower (-22.08 mg/dL, p = 0.24), and TNF-α dropped significantly (-178.62 fg/mL, p = 0.02). Heterogeneity was low-moderate for lipids/inflammation (I 2 = 0-64.65%) but high for blood pressure (I 2 = 87.39%). Discussion AGE marginally decreases cardiovascular risk factors, particularly inflammation (TNF-α), but has variable, dose-dependent effects upon blood pressure and cholesterol. Inconsistent doses and heterogeneity of the studies prevent definitive conclusions; future studies should use a standardised protocol. Conclusion There are dose-dependent cardiovascular benefits to supplementation with AGE, including reductions in TNF-α and possibly blood pressure and cholesterol. Larger, standardised studies are required to optimize the dosage for high-risk populations. Registered in PROSPERO (CRD420251033175).
IntroductionThioredoxin reductase 1 (TrxR1) is a key enzyme involved in maintaining redox homeostasis in cancer cells and is considered a promising target for anticancer drug development. This study aimed to rationally design, synthesize, and evaluate a novel series of oxazol-5(4H)-one derivatives as potent and selective inhibitors of TrxR1. MethodsThe design process was initiated by screening a commercial library of oxazolones, which informed the construction of a QSAR model. Guided by molecular docking studies against the TrxR1 catalytic site (PDB: 3EAN), a focused library of 18 target 4-benzylidene-oxazol-5(4H)-ones was synthesized via a multicomponent reaction using substituted hippuric acids and aromatic aldehydes. The inhibitory activity against TrxR1 and the off-target enzyme glutathione reductase (GR) was determined using a DTNB assay on A549 cell lysates. Cytotoxicity was evaluated against a panel of human cancer cell lines (A549, SHSY5Y, U251, and HELA) and normal HEK293T cells using an MTT assay. The mechanism of action was further investigated through immunoblotting analysis. ResultsSeveral compounds demonstrated potent and selective TrxR1 inhibition. Lead compounds 1i, 1o, and 1s exhibited significant TrxR1 inhibition (over 50% at 25 µM) with low activity against GR. The IC50 values for TrxR1 inhibition were in the nanomolar range (0.25 nM for 1i, 19.7 nM for 1o, and 4.2 nM for 1s). These compounds also showed pronounced cytotoxicity against cancer cells, with compound 1i being the most active against U251 glioblastoma cells (IC50 = 12.58 µM) and demonstrating selectivity over normal cells. Immunoblotting analysis confirmed that inhibitors containing dual Michael acceptor motifs (e.g., 1q-s) induced the formation of covalent TrxR1 dimers, indicative of a unique mechanism of action. DiscussionThe results validate our rational design strategy, highlighting the critical role of the Michael acceptor warhead and the oxazolone core in effective TrxR1 binding and inhibition. The high selectivity for TrxR1 over GR and the observed cytotoxic selectivity toward cancer cells underscore the therapeutic potential of this compound class. The discovery of TrxR1 dimerization provides a novel mechanism for irreversible enzyme inhibition. ConclusionA new series of oxazol-5(4H)-one derivatives was successfully developed as highly potent and selective TrxR1 inhibitors. The lead compounds 1i, 1o, and 1s showed promising anticancer activity in vitro, coupled with a favorable selectivity profile. This work not only establishes a robust structure-activity relationship but also introduces a rational strategy for designing novel TrxR1-targeted antitumor agents, supported by the discovery of a dimerization-based inhibition mechanism.
