In silico pharmacology最新文献

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.

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.

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.

Marburg virus (MARV) is classified as a risk group 4 pathogen by the WHO due to its high fatality rates, frequent person-to-person transmission, and lack of approved vaccines or treatments. This highlights the need for a universally effective MARV vaccine. In this study, we employed computational bioinformatics methods to analyze conserved sequences of the VP30 transcriptional activator, using databases and bioinformatics tools. Amino acid sequences were sourced from NCBI, and antigenicity was assessed using Kolaskar, Tongaonkar, and VaxiJen servers. B and T cell epitopes were identified using ABCPred and the Immune Epitope Database, providing insights into potential immunogenic regions. The VP30 protein, crucial in both physiological and pathological processes, emerged as a promising target for vaccine development. Key epitopes from VP30, including IGLPCTDGL and PCKIGLPCTIGLPCTD, showed efficacy as T and B cell epitopes. We designed a multi-epitope vaccine incorporating these epitopes, demonstrating favorable physicochemical and immunological properties. Molecular dynamics simulations confirmed that both mono- and multi-epitopes improve the vaccine's therapeutic potential. Our analysis suggests the proposed vaccine candidate could trigger an immune response against MARV. However, experimental validation is needed to confirm its immunomodulatory properties and effectiveness.

In this study, a series of indole-based derivatives (2a-f) was synthesized, followed by a Mannich base reaction from the starting materials, substituted phenylhydrazine and substituted acetophenone, in glacial acetic acid. All the synthesized derivatives were characterized by IR, NMR, Mass and screened for anticonvulsant activity using the maximal electroshock model. Among all, 2b, 2c and 2e exhibited potent anticonvulsant activity as compared to standard drug phenytoin sodium. In our study, we carried out an in-silico study against GABA receptor, and the AMPA-sensitive glutamate. Docking study revealed that 2b, 2c, 2e showed good binding energy against AMPA receptor. Among the six synthesized compounds 2b, 2c, and 2e were found to possess an optimum to excellent in- silico ADME properties. Our results showed that substituting a 2-phenylindole derivative also increases the therapeutic value of the 2-phenylindole core, which is needed for the discovery of a potent anticonvulsant agent.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00517-z.

Human coronavirus infections, particularly those caused by SARS-CoV-2, remain a significant public health concern. Researchers are actively exploring new antiviral compounds, including those derived from marine natural products. This study investigates fucoxanthin (FX) and its metabolites, fucoxanthinol (FXOH) and amarouciaxanthin A (AXA), as potential inhibitors of the SARS-CoV-2 nucleocapsid phosphoprotein (NP) using molecular docking. Molecular dynamics simulations were performed for 100 ns, along with the reference drug, ribavirin, for comparative purposes. Compared to ribavirin (- 5.870 kcal/mol), FXOH (- 5.662 kcal/mol), AXA (- 5.189 kcal/mol), and FX (- 4.594 kcal/mol), the binding energies were low. RMSD analysis revealed that the NP-ribavirin (1.4-3.8 Å) exhibit a more rigid protein confirmation. In constant, the NP-FX (2.4-4.8 Å), and NP-FXOH (2.5-4.5 Å) showed moderate fluctuations, reflecting the inherent flexibility of the protein. cDFT analysis (HOMO &LUMO) revealed that FX had higher electronic reactivity and charge-transfer capability, whereas FXOH showed greater electronic stability. From these observations, the FX and FXOH remained in the binding site during the MD simulation, and they can be used as an antiviral drug formulation. However, this study is limited to computational prediction, and further in vitro and in vivo investigations are needed to validate the efficacy, safety, and pharmacokinetic properties of ligands.

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