In silico pharmacology最新文献

To explore the key biomarkers and molecular mechanisms of Phellinus igniarius (Sanghuang, SH) in the prevention and treatment of prostate cancer (PCa). LC-MS/MS was used to identify 118 bioactive SH blood components, followed by target prediction. PCa-related genes were screened through differential expression analysis (DEGs) and weighted gene co-expression network analysis (WGCNA) by integrating disease databases and TCGA-PRAD data. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were then performed to reveal pathways. Machine learning algorithms were then used to screen core targets. Mendelian randomisation (MR) analysis was then used to identify key SH biomarkers against PCa. Molecular docking and dynamics simulations were then used to assess the binding characteristics between the key biomarkers and their corresponding active SH components. Finally, we examined the relationship between the key biomarkers and immune cell infiltration levels in the tumour microenvironment. KEGG enrichment analysis revealed a strong enrichment of these targets in the Rap1, Ras and MAPK signalling pathways. Five key SH targets against PCa were identified: FGFR2, GSTP1, FOLH1, TERT and CXCR2. Dataset validation confirmed significant differences in the expression of core targets in PCa tissues. Further MR analysis indicated that GSTP1 and CXCR2 may be key biomarkers for SH against PCa. Molecular dynamics simulations provided preliminary support for the binding stability between SH components and their targets. Meanwhile, immune infiltration analysis revealed correlations between these targets and immune cell populations. Together, these results offer insights into the potential roles of SH components in PCa treatment. SH may exert its anti-PCa effects by regulating key biomarkers such as GSTP1 and CXCR2, interfering with oncogenic signalling pathways including Rap1, Ras and MAPK, and modulating the infiltration levels of immune cells such as M0/M1 macrophages simultaneously.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00511-5.

Ficus capensis (FC) and Parquetina nigrescens (PN) are traditional African medicinal plants with reported neuropharmacological properties, yet their active compounds and mechanisms remain poorly characterized. This study employed an integrative experimental and computational strategy to compare their phytochemical profiles and neuroprotective mechanisms, aiming to identify multi-target therapeutic candidates. Phytochemical constituents were profiled using HPLC and GC, while in vitro neuroprotective effects were evaluated through cholinesterase inhibition and lipid peroxidation (LPO) assays. Network pharmacology, Gene Ontology, KEGG enrichment, molecular docking, and molecular dynamics (MD) simulations were conducted to uncover mechanistic pathways and prioritize key compounds. The top-performing FC ethanolic extract (FCET) and its major bioactive, luteolin, were further tested for HDAC1 inhibition and thermal target engagement. FC showed a richer neuroactive phytochemical profile than PN, and exhibited stronger inhibitory effects on acetylcholinesterase, butyrylcholinesterase, and LPO. Network pharmacology identified 304 neurodegeneration-related protein targets, highlighting AKT1, HDAC1, EP300, STAT3, and EGFR as core nodes, enriched in MAPK, PI3K-AKT, and Ras pathways. Luteolin ranked highest across these targets, outperforming native ligands in docking scores. MD simulations confirmed the stability of luteolin-target interactions, with RMSD values < 0.3 nm and minimal structural fluctuations. Luteolin and FCET also showed potent HDAC1 inhibition, confirmed by IC₅₀ values and significant thermal stabilization (ΔTm). These findings position Ficus capensis as a promising neuroprotective agent and luteolin as a viable multi-target lead compound. The study offers mechanistic insight into their therapeutic potential and supports further development of FC-derived agents for neurodegenerative disease intervention.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00557-z.

Diabetes mellitus often requires long-term therapy that can cause side effects, prompting interest in alternative approaches. Pumpkin seeds, traditionally used for their antidiabetic effects, are often combined with conventional drugs, raising concerns about potential interactions. The present study aimed to evaluate the possible interaction of ethanolic extract of pumpkin seeds with glibenclamide in streptozotocin-induced diabetic rats, supported by in-silico analysis. In-silico studies, including network pharmacology, gene ontology, and molecular docking, were performed to predict the multitargeting potential of pumpkin seed phytoconstituents against diabetes-related targets. Albino Wistar rats were injected with streptozotocin (45 mg/kg, i.p.) to induce diabetes and treated for 28 days with ethanolic extract of pumpkin seeds (200 mg/kg), glibenclamide (5 mg/kg), and their combination. Blood glucose levels and body weight were monitored periodically. At the end of the treatment, oral glucose tolerance, lipid profile, glycated hemoglobin, insulin, renal biomarkers, and histopathology of pancreas, liver, and kidney were assessed. In-silico analysis identified PIK3R1, STAT3, MAPK1, and ESR1 as key diabetes-related targets of pumpkin seed phytoconstituents, highlighting their multitargeting potential. Oral administration of ethanolic extract of pumpkin seeds, glibenclamide, and their combination significantly improved body weight, lowered blood glucose levels, enhanced glucose tolerance, and restored lipid and renal profiles, with combination therapy showing more pronounced effects. Histology confirmed preservation of pancreatic, hepatic, and renal integrity. Co-administration of ethanolic extract of pumpkin seeds and glibenclamide exerts synergistic antidiabetic effects, indicating its potential as an effective adjunct to conventional therapy for managing diabetes and its associated complications.

The U.S. Food and Drug Administration (FDA) approved resmetirom, a thyroid hormone receptor- β agonist in 2024 as the first drug for NASH with F2-F3 fibrosis. Nonetheless, rare adverse events such as idiosyncratic drug-induced autoimmune hepatitis (DI-AIH) have been reported, with unclear mechanisms. This study investigates the potential toxicological mechanisms of resmetirom in idiosyncratic DI-AIH using network toxicology combined with molecular docking. 26 core targets were identified, with the foremost five being SRC, PIK3CA, PIK3CD, HSP90AA1, and AKT1. These targets are involved in three immune-related signalling pathways, including T-cell receptor (TCR) signalling, C-type lectin receptor (CLR) signalling, and PI3K/Akt signalling. The predicted interaction of resmetirom with SRC may disrupt CLR signalling in dendritic cells, driving excessive IL-12 and IL-6 production and promoting Th1 and Th17 differentiation. Both TCR and CLR pathways critically converge downstream via PI3K/Akt, which serves as a shared hub. Dysregulation of PI3K/Akt may drive excessive IL-12 production in dendritic cells and may enhance inflammatory responses in T cells. Besides, disruption of HSP90 may further destabilize Akt, hence compromising PI3K/Akt pathway function. These dysregulated pathways may contribute to hepatocellular injury characteristic of DI-AIH. Molecular docking showed strong binding affinities between resmetirom and all identified core targets. Despite these computational predictions offer mechanistic insights into resmetirom-induced DI-AIH, experimental validation is crucial to confirm these findings. After validation, this work may help identify patients at risk and support precision medicine approaches in NASH treatment.

Eggshells hold long-lasting nutritional and medicinal relevance in African folklore, often administered traditionally in its crushed or powdered form to ameliorate bone issues, treat calcium deficiency, and promote well-being. However, not much has been achieved in translating this folklore practice into pharmaceutical exploration and formulation science. Drug-excipient incompatibilities are critical considerations in the development of stable and effective pharmaceutical formulations. This study investigated the compatibility of ibuprofen with eggshell-derived calcium citrate using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and molecular docking approaches. Calcium citrate was prepared from chicken eggshells via reaction with citric acid and characterised. Binary mixtures of ibuprofen and calcium citrate were evaluated for potential interactions using FTIR and DSC. In silico molecular docking studies were conducted using AutoDock Vina, and docking methodology was validated using re-docking of a known ibuprofen-calcium interaction. FTIR spectra of the binary mixtures showed minor peak shifts, particularly at 1710 cm^-1 (C=O) and 3300 cm^-1 (O-H), suggesting weak physical interactions. DSC thermograms demonstrated slight broadening and depression of the ibuprofen melting endotherm, indicating no significant incompatibility. Molecular docking revealed a binding affinity of - 4.7 kcal/mol, primarily mediated by ionic interactions between ibuprofen's carboxyl group and calcium ions. Ibuprofen exhibits acceptable compatibility with eggshell-derived calcium citrate. These findings suggest its potential as a sustainable and cost-effective pharmaceutical filler in oral drug formulations.

Pesticides are essential in modern Bangladeshi agriculture and public health, contributing to effective crop protection, disease management, and food safety maintenance. A widespread use of pesticides has raised health and environmental concerns, as highlighted by the World Health Organization (WHO). This study focused on six widely used pesticides in Bangladesh Acephate (ACE), Ametryn (AME), Carbaryl (CYL), Carbendazim (CZM), Dichloran (DLN) and Glyphosate (GLY) are selected for their extreme use and associated adverse health effects, including neurological and developmental toxicity, anorexia, respiratory paralysis, cancer, reproductive impairments, immunotoxicity, endocrine disruption and even mortality. Using computational approaches, we analyzed their physicochemical, spectral, biological, and toxicological properties. Quantum chemical analysis was conducted to evaluate changes in HOMO-LUMO energy gaps, electrostatic potential, enthalpy, and dipole moments, while molecular docking and nonbonding interactions revealed binding affinities against cancer-causing and human estrogen-related receptor proteins (PDB IDs: 2E2R and 4MNF). The 100 ns molecular dynamics (MD) simulations revealed that the compounds possess improved stability and flexible structural behavior. Overall, this study provides preliminary molecular insights into the toxicological hazards of commonly used pesticides in Bangladesh, highlighting their potential impacts on human health and the environment and reinforcing the need for public awareness and further experimental validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00566-y.

Rhizopus delemar 1,3-β-glucan synthase is a central enzyme in fungal cell wall biosynthesis and represents a critical target for antifungal intervention. Because its experimental structure is unavailable, we predicted the three-dimensional architecture of the enzyme using AlphaFold v2.2.0 and validated the model through structural superposition with the cryo-EM structure of Saccharomyces cerevisiae Fks1. The overall fold, including the regulatory, glycosyltransferase (GT) catalytic, and transmembrane domains, was conserved, supporting the reliability of the predicted model. Binding-site analysis, combined with structural alignment, confirmed that the primary druggable pocket lies within the GT catalytic groove. Virtual screening identified telmisartan as a promising inhibitor, which was further evaluated through a 100-ns molecular dynamics simulation. Stability metrics, principal component analysis, and free-energy landscape profiling indicated stable ligand accommodation, while MM/GBSA calculations revealed a favourable binding free energy of - 54.75 kcal/mol. Together, these results establish a validated structural framework for R. delemar 1,3-β-glucan synthase and identify telmisartan as a compelling lead scaffold for future antifungal optimization.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00546-8.

Colorectal cancer (CRC) is also among the most common and deadly malignancies in the world, which requires the creation of safer and more efficient therapeutic options. Mentha piperita, which has various pharmacological properties, was studied in its anti-CRC potential based on a detailed network pharmacology and molecular modelling study. Apigenin, Betulonic acid, b-ionone, Cosmosiin, d-borneol, and Hesperetin, six bioactive compounds, passed pharmacokinetics criteria and were associated with 155 targets of CRC. The analysis of protein-protein interaction revealed the major hub genes TNF-α, HSP90AA1, and ESR1. KEGG enrichment analysis identified major pathways related to CRC such as TNF-α signaling, PD-L1/PD-1 checkpoint, chemical carcinogenesis and thyroid hormone signaling. Molecular docking in molecular docking (average RMSD < 2.5 Å, Rg ≈ 20.2 Å). Betulonic acid (- 8.3 kcal/mol) and Cosmosiin (- 7.9 kcal/mol) were found to have high binding affinities with TNF-α, indicating their possible use in the regulation of tumor progression caused by inflammation. Their drug-likeness was supported by PK results of ADMET profiling that reported positive intestinal absorption (> 90%) and low toxicity levels. Besides, analysis of the expression showed that in advanced colon tumors, there were high levels of TNF-α (tumor necrosis factor-alpha) which were associated with a low survival rate. All of these quantitative results prove that Mentha piperita has multi-target treatment potential against CRC. Although the computational forecast of the computational predictions suggests that TNF-α related signaling is a viable mechanistic pathway, they are still predictive and need to be further validated in wet-labs in order to confirm its clinical significance.

This study explores the potential of selected natural products from Harungana madagascariensis (namely: harunganin anthrone, madagascin anthrone, harongin anthrone, harunmadagascarins-A, harunmadagascarins-B, kenganthranol-A, kenganthranol-B, kenganthranol-C, harunganol-A, harunganol-B, harunganol-D, harunganol E, harunganol-C, kengaquinone, madagascin, physcion, chrysophanol, madagascol, vismiaquinone-A, vismiaquinone-B, vismiaquinone-C, euxanthone, cadensin C, friedelan-3-one, lupeol, betulinic acid, kaempferol-3-O-β-D-glucopyranoside and methyl-3-formyl-2,4-dihydroxy-6-methyl benzoate) as inhibitors of bio-film formation response regulator (BfmR), a key virulence-associated response regulator in Acinetobacter baumannii (one of the ESKAPE pathogens).We employed integrative computational approach encompassing molecular docking, drug-likeness screening, ADMET profiling, molecular dynamics (MD) simulations, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy calculations for this assessment. Molecular docking indicated strong binding affinities at the BfmR homodimer interface, with the obtained docking scores surpassing that of the reference antibiotic, ofloxacin. Five top-performing compounds-harunganol-B, madagascin, madagascol, vismiaquinone-B and vismiaquinone-C were identified as potential inhibitors which showed properties compliant with Lipinski's Rule of Five. They also showed favorable gastrointestinal absorption and blood-brain barrier permeability profiles, as revealed by the BOILED-Egg model. MD simulations confirmed the structural stability of ligand-protein complexes, showing minimal RMSD and enhanced compactness and residue rigidity upon ligand binding. MM/PBSA analyses further supported the stability of the complexes, with harunganol-B demonstrating the most favorable binding free energy (ΔG_bind = - 50.12 kcal/mol). Overall, the computational data obtained underscore the promising inhibitory potential of these compounds, particularly harunganol-B, and highlighted their suitability for future in vitro and in vivo validation as lead scaffolds in anti-A. baumannii drug development.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00558-y.

Staphylococcus aureus, a major human pathogen, exhibits strong survival abilities both inside and outside host cells. The increasing prevalence of antibiotic-resistant strains presents a major challenge to modern medicine. Bioactive compounds from medicinal plants represent a potential alternative, owing to their diverse secondary metabolites. This study employed in silico docking and molecular dynamics simulations to identify bioactive compounds from medicinal plants targeting the virulence protein clumping factor A (ClfA) of S. aureus. Phytocompounds from Breynia retusa, Hemigraphis alternata, Imperata cylindrica, Oldenlandia corymbosa, Sida rhombifolia, Scoparia dulcis, Tephrosia purpurea, and Wrightia tinctoria were screened for pharmacokinetic properties, followed by molecular docking and dynamics simulations. Indirubin from W. tinctoria exhibited strong binding affinity for ClfA, with stable interactions confirmed by molecular dynamics simulations. Antibacterial assays using fresh and dry W. tinctoria leaf extracts demonstrated significant inhibition of S. aureus. GC-MS analysis identified 50 bioactive compounds, further supporting the plant's potential as a natural antimicrobial source. These findings highlight W. tinctoria, particularly indirubin as a promising candidates for developing anti-staphylococcal and wound-healing agents, warranting further in vivo validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00545-9.