Pharmacological potential of chalepensin from Ruta chalepensis L.: Acute toxicity and in vivo antitumor activity in the L5178Y-R murine model.

Naturally occurring C-C and C-O-C-linked biflavonoids as potential inhibitors of the SARS-CoV-2 main protease (Mpro).

Investigation of derivatives of 2H-chromene oximes as anticancer agents.

Cucurbita maxima (pumpkin) leaves have been traditionally used in folk medicine for the treatment of inflammation, fever, and oxidative stress-related disorders. However, scientific validation of these claims remains limited. This study aimed to evaluate the anti-inflammatory, antioxidant, and protective effects of C. maxima leaf aqueous extract and to elucidate its phytochemical composition and molecular mechanisms of action. The phytochemical profile of the aqueous extract was determined using UPLC-ESI-MS/MS analysis. In vivo anti-inflammatory activity was assessed in a benzylthiouracil-induced inflammation model by measuring white blood cell (WBC) counts, C-reactive protein (CRP) levels, and histopathological changes in liver and kidney tissues. In vitro anti-inflammatory potential was evaluated through the protein denaturation inhibition assay, using diclofenac as a reference. Pharmacokinetic and toxicity properties of major compounds were predicted using ADMET tools, while molecular docking studies were performed to evaluate interactions with COX-1 and COX-2 enzymes. UPLC-ESI-MS/MS analysis revealed a complex mixture of polyphenols, with caffeic acid (56.04%), rutin (9.25%), ferulic acid (8.79%), and myricetin-3-rhamnose (8.62%) as the main constituents. The extract significantly reduced inflammation by normalizing WBC counts (from 7.2 to 4.5×109/L), lowering CRP levels (from 630 to 220mg/L), and protecting liver and kidney tissues. The extract also inhibited protein denaturation in vitro (IC50=2.976mg/mL) compared to diclofenac (IC50=0.718mg/mL). Molecular docking revealed that major flavonoids exhibited strong binding affinities toward COX-1 and COX-2, often surpassing diclofenac, supported by stable hydrogen bonding and hydrophobic interactions. ADMET and toxicity predictions indicated good intestinal absorption for several major compounds, absence of predicted hepatotoxicity or skin sensitization, and generally low acute toxicity, with high predicted LD50 values and no mutagenic risk for most constituents. These findings support the traditional use of C. maxima leaves in folk medicine for the management of inflammation-related conditions, fever, and associated oxidative stress. Further isolation of the key active constituents and clinical evaluation are recommended to confirm their therapeutic efficacy.

Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation.

Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer's agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways.

Safe and clinically useful therapeutic drug delivery systems must be developed to fight fatal diseases and disorders like cancer, hypertension, and diabetes, among others. However, these systems face significant development challenges due to their solubility, stability, permeation, cytotoxicity, drug entrapment, and loading issues. Imitations can be avoided by creating innovative drug delivery systems based on nanomaterials, such as nanoclays. As layered nanostructures, nanoclays have many advantageous qualities, such as chemical inertness, colloids (dispersed in blood plasma), a large surface area, and viscosity. Nanoclays are qualified for use as a drug delivery carrier for anti-cancer, antihypertensive, antioxidant, and anti-diabetes medicines based on these qualities. This study discusses the evolution and use of nanoclay in drug delivery research. Clays of various sorts (kaolinite, halloysite, and montmorillonite) have been employed to generate prolonged and targeted drug delivery with enhanced pharmacokinetic characteristics. The modified clay demonstrated optimal drug loading, trapping, release, electrostatic interaction (van der Waals interaction), ion exchange reaction, and immobilization. Finally, nanoclay was employed to create a drug delivery system with enhanced pharmacokinetic properties for proteins, DNA, and pharmaceuticals. Many earlier research investigations have also reported its usage in bio-imaging, tissue engineering, gene transfer, and stem cell separation.

Pharmacophore-based virtual screening, molecular dynamics simulations, and bioactivity validation for JAK1/TYK2 dual inhibitors

Bioprospection of Piliostigma thonningii ethanol extract for anti-fibroid activity via molecular docking and in vivo hormonal evaluation in female wistar rats.

Synthesis, molecular docking, toxicity profile and antidiabetic properties of new dipeptide Sulfonamide bearing carboxamides

Structural and functional insights into glycosyltransferase from Nocardia asteroides NCTC11293 and structure-guided discovery of marine and phytochemical leads through pharmacokinetic screening and molecular dynamics studies.

This study aims to identify potential azole-derived inhibitors targeting the PI3K/AKT/mTOR signaling pathway involved in autophagy regulation and cancer progression. A structure-based virtual screening approach was employed using molecular docking, molecular dynamics (MD) simulations, and free energy calculations (MMGBSA and MMPBSA). The pharmacokinetic profiles and toxicity of lead compounds were assessed using ADMET analysis. In vitro validation was performed using MTT and MDC staining assays on MDA-MB-231 breast cancer cells.Among the screened compounds, KR4 demonstrated strong binding affinity towards all three kinases (-8.289, -5.222, and -6.331 kcal/mol) respectively with favorable pharmacokinetic properties. MD simulation confirmed the stability of the KR4-protein complexes, while post-MD MMPBSA analysis validated the binding energetics. In vitro studies revealed dose-dependent cytotoxicity of KR4 (IC₅₀ ≈ 39 µM) and induction of autophagy in treated cells. The integration of in silico and in vitro approaches highlights KR4 as a promising multi-target inhibitor of the PI3K/AKT/mTOR pathway with potential anti-cancer properties. These findings support further exploration of KR4 for therapeutic development.

Targeting Pseudomonas aeruginosa virulence has gained significant attention as a promising strategy to control its pathogenicity, lower the risk of resistance development and improve the effectiveness of current antibiotics. This virulence is controlled by an intricate quorum-sensing system, with PqsR serving as a key regulatory hub. PqsR has gained attention as a promising therapeutic target, with multiple studies reporting that its disruption markedly reduces virulence and impairs biofilm development. This review synthesizes findings from approximately twenty major medicinal chemistry studies published over the past five years to guide the rational design of next-generation PqsR antagonists targeting multidrug-resistant Pseudomonas aeruginosa. We summarize efforts that yielded forty-six inhibitors with IC50 values ranging from 0.005 μM to 32 μM, emphasizing scaffold development, SAR insights, and optimization strategies that significantly enhanced potency. Importantly, we also examine the pharmacokinetic properties of the most active analogues, identifying key liabilities that currently limit their translational potential. Additionally, we discuss emerging natural products as promising PqsR inhibitors, offering structural diversity and multi-target activity that can inspire broad-spectrum anti-virulence agent design. Finally, we outline future optimization strategies to enhance the potency and drug-like properties of scaffolds with moderate potency, thereby expanding the landscape of viable PqsR-targeted therapeutics.

Discovery of new non-macrocyclic TRK inhibitors based on conformational flexibility and scaffold hopping to overcome clinical acquired resistance.

Integrating synthesis, pharmacological evaluation, and molecular dynamics simulation of novel 8-substituted theophylline hybrids as potential PDE-4B inhibitors, bronchodilators and antibacterial.

Prostate cancer (PCa) remains a major global health challenge and is among the most frequently diagnosed malignancies in men. While early-stage PCa often progresses slowly, advanced disease is associated with significant morbidity and remains difficult to treat due to therapeutic resistance and limited efficacy in metastatic settings. Epigenetic modulation, particularly through inhibition of histone deacetylases (HDACs), has emerged as a promising therapeutic strategy. HDACs regulate gene expression and essential cellular processes by controlling the acetylation status of histone and non-histone proteins. Their dysregulation contributes to PCa progression, notably through aberrant androgen receptor signalling, a key driver of the disease. Histone deacetylase inhibitors (HDACis) exhibit antitumor activity by inducing apoptosis, causing cell cycle arrest, and inhibiting angiogenesis, particularly in haematological malignancies. However, monotherapy in solid tumours such as PCa has produced limited clinical benefit due to resistance mechanisms, incomplete therapeutic responses, and adverse effects that hinder sustained treatment. Notably, combining HDACis with chemotherapeutic or targeted agents has demonstrated synergistic potential, as HDAC inhibition can sensitize tumour cells to cytotoxic stress by altering chromatin structure, enhancing DNA damage responses, and reactivating silenced tumour suppressor genes. To fully harness their therapeutic potential, further studies are needed to improve the pharmacokinetic properties, isoform selectivity, and to identify predictive biomarkers for patient stratification. Advancing HDACi-based combination strategies may ultimately overcome current treatment barriers and improve clinical outcomes in PCa management.

Deprescribing antidepressants for children and adolescents should be guided by data as well as observation of the patient's relapse and withdrawal symptoms, according to a new study. Clinicians should also consider the pharmacokinetic and pharmacodynamic properties of medications, including when and how to initiate deprescribing, the researchers add. These considerations are critically important to the clinician‐family‐patient relationship.

Enterococcus faecium, a member of the ESKAPE pathogens, has become a significant clinical threat due to its rapidly increasing resistance to frontline antibiotics. This gram-positive bacterium has developed multidrug resistance through prolonged exposure to hospital environments, posing serious risks to immunocompromised patients. The present study aimed to identify novel therapeutic targets from the E. faecium genome and to explore the potential of marine natural products as anti-quorum sensing agents. A comprehensive subtractive proteomics pipeline incorporating non-human homology, essentiality, subcellular localization, druggability, and pathway uniqueness identified the accessory gene regulator A protein (AgrA) as a key target involved in quorum sensing, biofilm formation, and virulence. Following structural quality assessment, a hierarchy-based virtual screening of MNPs from the CMNPD and SPECS natural product libraries was carried out to identify potential AgrA inhibitors. The virtual screening workflow shortlisted three promising MNPs (CMNPD6428, CMNPD30814, and SPECS AE-765) with favourable binding affinities and pharmacokinetic properties. Docking scores ranged from - 7.46 to - 8.01kcal/mol, and MM/GBSA binding free energy calculations (≤ - 50kcal/mol) further supported their strong interactions. Pharmacokinetic evaluation indicated acceptable safety profiles. Density functional theory analysis confirmed the chemical stability and reactivity of the compounds through HOMO-LUMO energy gap assessment. Finally, 500ns molecular dynamics simulations and principal component analysis-based free energy landscape mapping validated the structural stability and sustained binding of the identified MNPs within the AgrA binding pocket. Overall, this study highlights three promising MNPs as potential anti-quorum sensing leads against E. faecium, offering a foundation for future therapeutic development.

Cathepsin S (Cat S) is a cysteine protease broadly expressed in the brain and a key mediator of neuroinflammatory processes, making it an attractive target for molecular imaging agents and drug development. Here, we report the development and evaluation of [18F]LY3000328, a positron emission tomography (PET) radiotracer that selectively targets Cat S and is derived directly from the clinical Cat S inhibitor LY3000328. [18F]LY3000328 was synthesized via a ruthenium-assisted late-stage 18F-deoxyfluorination of the corresponding phenol precursor. In vitro autoradiography, the marked reduction in tracer uptake under blocking conditions suggests specific binding of [18F]LY3000328 to Cat S, and the significantly higher uptake in transgenic 5xFAD mouse brain sections indicates upregulation of Cat S in Alzheimer's disease (AD), consistent with previously reported findings. However, in vivo PET imaging in wild-type mice revealed low blood-brain barrier (BBB) penetration and no significant reduction under blocking conditions, suggesting that limited BBB permeability may constrain its efficiency as a brain PET tracer. Despite its limited brain penetration, these results suggest that [18F]LY3000328 may serve as a useful starting scaffold for further optimization of physicochemical and pharmacokinetic properties toward Cat S-targeted PET imaging of neuroinflammation in AD and potentially other neurodegenerative disorders.

Squaramides (SQA) were reported as potent antituberculosis drugs through inhibition of the mycobacterial enzyme adenosine triphosphate (ATP) synthase, which is critical for ATP synthesis. However, squaramide compounds showed high metabolic clearance (CL) despite their promising potency and selectivity. Herein, we describe lead optimization efforts to improve the potency and metabolic stability of previous lead 1f. Multiple squaramide analogues exhibited improved potency. The most potent analogue 20j expressed enhanced potency of 51 nM and moderate metabolic stability. SQA 6k displayed optimum balance of potency and metabolic stability both in vitro and in vivo. Notably, against bedaquiline-resistant Rv0678 mutants, a modest 2-fold increase in 6k minimum inhibitory concentration (MIC) was observed─reversed by complementation─versus a 16-fold shift in bedaquiline (BDQ) MIC. In a chronic tuberculosis (TB) mouse model, 6k coadministered with 1-aminobenzotriazole (ABT) exhibited bactericidal activity. These findings provide key strategies for improving potency and pharmacokinetic properties toward a tractable preclinical candidate.