In silico pharmacology最新文献

Heat stress significantly disrupts physiological and molecular balance in poultry, leading to oxidative damage, inflammatory responses, and metabolic dysregulation. Among emerging solutions, phytogenic adaptogens have shown promise as natural agents that enhance resilience against these environmental challenges. This exploratory study examined the transcriptomic effects of Phytocee™, a proprietary phytogenic formulation, in heat-stressed broilers, alongside in silico predictions of its phytochemical interactions with longevity-associated pathways. Phytocee™ consists of a formulation of adaptogenic medicinal plants. The primary bioactive components contributing to these adaptogenic properties include hydrolyzable tannins, withanolides, and triterpenoids. Comprehensive identification, quantification, and confirmation of these phytochemicals were conducted using liquid chromatography-mass spectrometry (LC-MS), and the formulation's integrity was validated through high-performance liquid chromatography coupled with photodiode-array detection for routine quality assurance. The transcriptomic analysis demonstrated that heat stress led to the upregulation of several vital DNA repair and cell cycle regulatory genes, including FANCF, BRCA1, and EXO1. The supplementation of Phytocee™ resulted in further increases in these genes, reaching a log2 fold change of 1.32 with a significance level of p < 0.013. Additionally, resilience markers against oxidative stress such as SOD2, CAT, HSP25, HSPA2, and SOD3 along with metabolic adaptation indicators like IDH3A, ATP6V0D2, RRM2, ME1, FADS2, ALDH1L2, and DHCR7 showed significant enhancement post-treatment. There was also a restoration of several downregulated protective genes, including NFKBIA and BIRC5. DIGEP-Pred 2.0 and pathway enrichment were used in the in-silico analyses, which predicted that the key Phytocee™ phytochemicals interact with FOXO, AMPK, SIRT1, and mTOR network components. Transcriptomic patterns, such as upregulated DNA repair, oxidative resilience, and metabolic genes correlatively overlapped with this prediction. Again, no model validation or functional activation was performed. This exploratory study contributes to a hypothesis-producing framework for these associations to be tested in heat-stressed broilers but has several limitations related to the correlative nature of findings, absence of confirmation at the protein level, or functional assays, such as autophagy or pathway inhibition or direct measures of thermotolerance or production. Thus, confirmatory studies are warranted to test these implied mechanistic associations.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00589-5.

This study evaluated in silico the antifungal potential of phytochemicals from the leaves of Anacardium occidentale (cashew tree) against key enzymatic targets: farnesyltransferase (CnFTase), beta-carbonic anhydrase (β-CA), and adenylosuccinate synthetase (AdSS) from Cryptococcus neoformans. Molecular docking simulations were conducted to evaluate the binding affinity of selected compounds to key enzymatic targets. The protein structures were retrieved from the Protein Data Bank (PDB) and prepared using AutoDockTools™, while molecular docking was performed with AutoDockVina. Molecular dynamics simulation was performed using the iMODS server, in order to check the stability as well as mobility in the receptor-ligand complexes following molecular docking. Additionally, ADME-Tox properties were predicted using a consensus approach combining ADMETlab 3.0 and ADMET-AI, assessing parameters such as permeability (PAMPA), metabolism (CYP450), and clearance (Cl _{int, u}, Cl _Micro, Cl _Hepa). The structural complexity of the ligands was analyzed using the MCE18 score, allowing the identification of compounds with an optimal balance between drug-likeness and synthetic accessibility. Notably, quercetin 3-galactoside, tricetin 3'-xyloside, and kaempferol 4'-glucoside exhibited favorable pharmacokinetic profiles and docking affinities, suggesting their potential as antifungal candidates. A PAMPA profile is estimated for these compounds based on a moderate permeability in more selective cells (High Papp MDCK) and low hepatic clearance, resulting from metabolic stability. Molecular docking studies showed that lead compounds have excellent affinity and specificity for the enzymes CnFTase and AdSS (affinity energy <-6.0 kcal/mol), interacting with the binding sites of the drug Fluconazole. Molecular dynamics simulations indicated a smaller conformational torsion of the Cα of the CnFTase and AdSS structures, suggesting that collective movements for both protein-ligand complexes are stable. The results suggest that these lead compounds are a starting point for new glycosylated drugs inhibiting Cryptococcus neoformans.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00590-y.

Diabetes is a long-lasting condition of glucose metabolism caused by abnormalities in insulin secretion and effectiveness. Type 2 diabetes with persistent hyperglycemia, managed with various hypoglycemic medications, has severe adverse effects and can harm vital organs. Anti-diabetic medication from Indian traditional medicinal plants has shown no such side effects. The current study aimed to explore and assess the antidiabetic potential of terpenoid phytocompounds from two types of Gymnema sylvestre extracts. The current study utilized various analytical methods to validate anti-diabetic phytocompounds from Gymnema sylvestre; further, it will be confirmed by studying its crucial interaction with diabetic target proteins. GCMS analysis of Gymnema sylvestre revealed compounds, most notably terpenoid compounds. In vitro anti-diabetic validation reveals that Gymnema sylvestre chloroform leaf extract possesses equipotent anti-diabetic potential (IC50 15.20 ± 0.92 µg/ml and 12.20 ± 0.52 µg/ml) when compared with the standard drug acarbose (IC50 11.20 ± 0.72 µg/ml and 9.40 ± 0.42 µg/ml) against alpha amylase and alpha glucosidase enzymes, respectively. Further in silico docking analysis of phytocompounds from Gymnema sylvestre against three diabetic target proteins (alpha amylase, aldose reductase, and alpha glucosidase) revealed that Gymnemic Acid I exhibits higher binding affinity with alpha amylase with a docking score of - 10.3 kcal/mol than the standard drug acarbose (- 8.7 kcal/mol). Top-scored terpenoid compounds from Gymnema sylvestre were screened for further ADMET and DFT analyses along with the standard drug acarbose, and their results revealed that terpenoid compounds showed good pharmacokinetic and DFT indices. Finally, four complexes, 1B2Y-gymnemic acids, 1B2Y-acarbose, 1US0-lupeol, and 1US0-acarbose, screened for MDS and MMGBSA analysis, revealed good number of hydrogen, hydrophobic, water bridges interaction and interaction fractions through their simulation trajectories of screened ligand with anti-hyperglycemic target proteins. The findings of this study reveal that terpenoid compounds from Gymnema sylvestre possess anti-diabetic potential and bring new improvements for alternative medicine in the treatment of diabetes.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00573-z.

The worldwide illnesses are stress and disorders associated with stressors. This research work checks the anti-stress capability of Olea europaea leaf extract in ethanol as an in vivo and in silico anti-stress agent. Molecular docking and ADMET studies show that most plant components have excellent intermolecular interactions with protein receptors and show drug-like properties. The LD₅₀ of Olea europaea is safe up to 1000 mg/kg body weight per oral (p.o.) weight found in acute oral toxicity. As a result, we selected 400 and 600 mg/kg as the two dosages for anti-stress activity in the current investigation. Antistress activity: when compared to normal and unpredictable spontaneous stress groups in a dose-based manner, the results show a corresponding decline in MDA and MPO levels and a rise in GSH, CAT, and SOD levels when stress models containing Olea europaea leaf extract and Geriforte Syrup are used in the unpredictable spontaneous stress model. The histological analysis shows significant recovery from cardiac, stomach, and brain injuries. Improved tissue architecture and decreased inflammatory and degenerative alterations demonstrated the dose-dependent (400 & 600 mg/kg) cardioprotective, gastroprotective, and neuroprotective benefits of treatment with OE ethanolic leaf extract. The brain, stomach, and heart tissues healed nearly normally at the higher dosage. These protective effects were similar to those seen with conventional Geriforte therapy. Because Olea europaea leaf extract contains phenolic components, specifically iridoids and secoiridoids, as well as antioxidant molecules including ligstroside, oleuropein, hydroxytyrosol, tyrosol, and caffeic acid, the results showed the potential anti-stress action of the extract.

Cancer remains a leading cause of death, with limited effective therapies. The AXL-GAS6 pathway promotes tumor growth, invasion, metastasis, and resistance to apoptosis. Large Language Models (LLMs) can predict drug-target interactions, generate novel molecular scaffolds, and optimize lead compounds. This study aims to design novel small molecules through a computational pipeline integrating commercial LLMs, molecular docking, molecular dynamics (MD), and ADMET evaluation. We combined DeepSeek LLM with conventional computational methods to design AXL inhibitors via three strategies: natural product-based, microbiome-derived, and FDA-approved drug-inspired scaffolds. Structured prompt engineering generated novel candidates, filtered for drug-likeness, synthetic feasibility, and docking score (Glide, Schrödinger). Top hits underwent 100 ns MD simulations and ADMET evaluation (SwissADME, ADMETLab3). AIC1 showed the highest binding affinity (- 10.079 kcal/mol), surpassing clinical-stage bemcentinib (- 8.234 kcal/mol). MD confirmed stable complexes (RMSD < 3 Å), with AIC1 and AIC4 forming extensive hydrogen bonds. ADMET profiling indicated favorable pharmacokinetics for all, with AIC2 exhibiting the lowest toxicity (hERG inhibition: 34.2%, hematotoxicity: 36.8%) and optimal drug-like properties. This work pioneers LLM-driven in silico design of AXL inhibitors, offering a scalable blueprint for accelerated anticancer drug development.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00582-y.

Medicinal plants remain a valuable source of structurally diverse natural products with therapeutic potential. Tapinanthus globiferus (Loranthaceae) is widely used for the treatment of cancer-related conditions, yet its chemical and pharmacological basis remains poorly defined. In this study, phytochemical profiling, cytotoxicity testing, and computational analyses were employed to characterize the bioactive potential of T. globiferus leaves. The leaves were subjected to extraction using 70% methanol and subsequently fractionated using butanol. The butanol fraction demonstrated notable cytotoxic activity against HT29 colon cancer cells, consistent with morphological evidence of apoptosis. High-performance liquid chromatography with diode array detection (HPLC-DAD) revealed the presence of abundant phenolic and flavonoid constituents, including kaempferol and quercetin derivatives, rutin, isoquercetin, catechin, and protocatechuic acid, which were identified as candidate marker compounds. To explore mechanisms, major identified compounds were docked in silico to VEGF-A and the anti-apoptotic protein BCL-2. Rutin, trifolin (a kaempferol glycoside), and epigallocatechin exhibited the strongest binding (e.g. rutin: - 8.85 kcal/mol to VEGF-A), surpassing the reference inhibitor Pazopanib (- 3.56 kcal/mol) with multiple stabilizing interactions with these proteins, suggesting potential to interfere with tumor angiogenesis and cell survival pathways. Collectively, these findings provide a scientific basis for the traditional use of T. globiferus and support its fraction as promising sources of multi-targeted anticancer agents. The identification of bioactive compounds further establishes a foundation for bioassay-guided isolation, mechanistic validation, and future drug development.

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern with no specific approved pharmacological treatments. While Hibiscus sabdariffa (HS) shows therapeutic potential, its multi-target molecular mechanism remains unelucidated. This study pioneers a highly novel and integrated computational strategy combining network pharmacology, validated structure-based pharmacophore modeling, molecular docking, molecular dynamics simulations (MDs), and binding free energy calculations. Utilizing a unique and comprehensive compound library of HS phytochemicals, this rigorous methodology offers superior accuracy for mechanism elucidation. Network analysis revealed that HS primarily modulates the Lipid and Atherosclerosis pathway. A key novel finding was the identification of ten regulatory hub targets, including the critical components AKT1, MAPK1, MAPK3, CASP3, JAK2, MAPK14, EGFR, mTOR, IGF1, and IL6. By developing specific pharmacophore models for these targets, we stringently screened the compound library, successfully pinpointing four top-scoring phenolic constituents: P16 (blestrin A), P21 (dendrocandin I), P29 (octahydrocurcumin) and P32 (tribulusamide B). MDs confirmed these compounds possess superior binding affinities, predicting their function as potent multi-target agents against NAFLD. This work is the first to systematically propose the multi-target mechanism of HS, pinpointing these specific, high-affinity phytochemicals and their associated molecular hubs. These findings provide a robust molecular foundation, prioritizing these HS-derived compounds and targets for subsequent in vitro and in vivo experimental validation to accelerate the development of novel NAFLD therapeutics.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00577-9.

The increased interest in natural products as a source of therapeutic agents has necessitated this research work on the bioactive potential of Sechium edule (Jacq.) Sw (S. edule) leaf extract. The antimicrobial activity of the petroleum ether extract of S. edule was determined using a combined in vitro and in silico approach. Phytochemical screening revealed the presence of bioactive alkaloids, flavonoids, terpenoids, and saponins. Twenty-three (23) compounds were characterized using gas chromatography-mass spectrometry (GC-MS) analysis, the major ones being hexadecanoic acid, butyl ester (15.11%), N-benzyl-N-hexadecanamide (12.31%), hexadeca-7, 10, 13-trienoic acid (10.21%), and methyl stearate (7.62%). The extract demonstrated zones of inhibition ranging from 15 to 20 mm against Staphylococcus aureus, Escherichia coli, vancomycin-resistant enterococci, Candida albicans, and Candida stellatoidea, while Helicobacter pylori showed resistance. The minimum inhibitory concentration (MIC) was 2.5 mg/mL. The in silico drug-likeness assessment revealed that all the compounds adhered to the rule of five as defined by Lipinski. Pharmacokinetics profiling indicated good intestinal absorption, minimal cytochrome P450 inhibition, moderate clearance, and mixed toxicity. The non-toxic compounds were further screened using a molecular docking approach. The compounds had good binding affinities with microbial target proteins PDB ID: 3Q8U (S. aureus), 1FJ4 (E. coli), and 5FSA (C. albicans) with the scores varying between - 4.3 and - 7.8 kcal/mol. The scores were marginally lower than those of standard antimicrobial drugs (fluconazole and ciprofloxacin). These findings present the extract as a promising source of antimicrobial agent with a favourable pharmacokinetic profile, which should be further subjected to potential clinical prospects.

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Comparative analysis of protein-ligand interactomes is crucial for understanding binding specificity, drug efficacy, and the impact of structural changes such as mutations. However, comparing the full spectrum of non-covalent interactions between different complexes often requires manual data extraction and complex workflows. We developed juProt, an open-source web application, to automate and streamline the comparative analysis of the complete protein-ligand interactome. juProt is developed in Julia using the Genie.jl framework and integrates the Protein-Ligand Interaction Profiler (PLIP) for comprehensive interaction detection. Users can either upload local PDB structures or automatically fetch files directly from the RCSB PDB using PDB IDs. The application detects and compares the full range of non-covalent interactions, including Hydrogen Bonds, Hydrophobic Contacts, π-Stacking, Salt Bridges, and Water Bridges. It generates comparative outputs including quantitative metrics, fold-change calculations, and 2D spatial pocket projections to visually map the geometric distribution of interacting residues. Validation against standalone PLIP using 20 diverse protein-ligand complexes (experimental and docked) demonstrated 100% concordance across all supported interaction types. A case study on human aromatase and its inhibitors (Letrozole, Anastrozole) interacting with native and mutant forms showcased juProt's utility. The analysis revealed that the Met364Thr mutation significantly remodeled the hydrophobic core of the Letrozole binding site, a structural insight clearly illustrated by the comparative 2D spatial mapping. juProt offers a robust, user-friendly methodology for the comparative analysis of the complete protein-ligand interactome. By automating data retrieval, calculating quantitative fold-changes, and generating spatially explicit 2D pocket projections, it significantly lowers the barrier for comprehensive structural analysis without requiring specialized graphics software. The tool is freely available at juprot.info.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00588-6.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly transmissible novel coronavirus, sparked the global pandemic, COVID-19, in 2020. Research primarily targeted specific drugs to block this virus, with natural products emerging as promising and reliable treatments. Lichens represent a valuable source of antiviral drugs. Specific secondary metabolites present in lichens with known antiviral properties have been researched. The current work focussed on the molecular docking of antiviral compounds from lichen against two possible targets, the main proteases of the SARS-CoV-2 virus (Mpro PDB ID: 6W63 and 6Y84). Other drugs were evaluated to the same possible targets to compare their inhibitory effects against proteins and identify particular medication for the treatment of COVID-19. Additionally, Molecular dynamics simulation and ADMET prediction was carried out. The docking results showed that alectorialic acid with 6Y84 and 6W63 had a docking score of -10.92 kcal/mol and - 14.34 kcal/mol, respectively. Molecular dynamics simulation of the alectorialic acid with target protein complexes for 500 ns confirm the reliability of the drug and compound's binding capability to the target. Our findings suggest that alectorialic acid, a bioactive compound from lichen, is a potential drug for COVID-19 treatment.

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