In silico pharmacology最新文献

Colorectal cancer (CRC) is a multifactorial malignancy frequently driven by aberrant activation of the Wnt/β-catenin cascade, which promotes uncontrolled cell proliferation and tumor progression. Tankyrases (TNKS1/TNKS2), members of the PARP family, regulate this pathway by mediating AXIN degradation, thereby stabilizing β-catenin. Inhibition of TNKS can restore AXIN levels and attenuate Wnt signalling, positioning TNKS as a promising therapeutic target. Leveraging the structural diversity, biochemical specificity, and evolutionary refinement of natural microbial compounds, this study screened 36,588 microbial and fungal natural products obtained from the NPATLAS database. High-throughput screening was carried out using Python and the RDKit package, applying stringent physicochemical, structural, and drug-likeliness filters. Exhaustive virtual screening, molecular docking, and 300 ns molecular dynamics (MD) simulations identified two promising candidates, namely Malassezione (NPA018503) and Xenocockiamide B (NPA033189), which exhibited the most favourable and stable binding interactions with TNKS-1, with binding affinities of - 11.45 kcal/mol and - 12.48 kcal/mol, respectively. Further validation through MM-PBSA calculations, Principal component analysis (PCA), DCCM, and free energy landscape (FEL) analyses revealed robust conformational stability and distinct clustering mechanisms of these top hits within the TNKS-1 active site. Density functional theory (DFT) calculations additionally confirmed favourable electronic characteristics for both compounds, including optimal HOMO-LUMO energy gaps and chemical reactivity parameters. Pharmacokinetic profiling indicated high GI absorption, metabolic resilience, and minimal toxicity risk. Although XAV939 is a known TNKS-1 inhibitor, it demonstrated comparatively reduced efficacy across binding and stability metrics. In conclusion, this integrative computational evidence supports microbial-derived compounds as promising natural candidates for TNKS-1 inhibition, offering a new avenue for in vivo validation and structure-guided discovery of next-generation microbe-based therapeutics for colorectal cancer.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00585-9.

In the fight against contagious diseases, COrona VIrus disease 2019 (COVID -19) has been a formidable oponent. The SARS-CoV-2 virus, the etiological agent of COVID-19 continues to pose global health risks due to the ongoing mutations and post-COVID complications. Inhibiting the binding site of the SARS-CoV-2 Main Protease (M^Pro), with suitable inhibitors represents a promising therapeutic strategy to contain the pandemic. Flavonols, a class of flavonoid phytochemicals, exhibit a wide spectrum of biological activities. In this study, we assessed the inhibitory potential of 15 flavonols, using a multifaceted computational approach that included PASS prediction, molecular docking, Molecular Dynamics (MD) simulations and ADMET analysis. Our results identified Kaempferol as a potent M^Pro inhibitor, characterised by minimal RMSD, minimal RMSF and optimal Rg values. Furthermore, Kaempferol exhibited a superior safety profile and good oral bioavailability, outperforming the FDA-approved antiviral-Molnupiravir.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00574-y.

The modern era has widely realized and accepted the significance of the vast plant resources for probing several safe and effective therapeutic products and addressing promising solutions to various health concerns. In search of a potent, non-toxic, and low-cost natural compound, Artocarpus heterophyllus L. latex was studied as a suitable and promising choice due to its inherent biological properties conferred by several secondary metabolites. The GC-MS results of the latex, resin, and residual fractions reported the presence of some diterpenes and diaziridine compounds, indicating their potential pharmacological role in the material. The successful elimination of saponins from the resin and its increased thermal stability were inferred from the characterisation of the latex and its fractions by FT-IR, XRD, and DSC-TGA. Molecular docking analysis of the molecules identified from the GC-MS profile with anti-inflammatory proteins such as TNFα, COX2, IL10, and iNOS, and antioxidant markers such as SOD and catalase, were carried out. It was found that compounds such as diaziridine, mannosamine, undecane, and adamantane compounds exhibited an impressive dock score between -5 and -7 kcal/mol. The combined resin-residual fraction exhibited the most potent antioxidant and anti-inflammatory activities, with IC₅₀ of 0.56 and 0.46 mg/ml, respectively. The resin and the combined resin-residual fraction exhibited better antimicrobial activity against all the tested microorganisms (E. coli, Staphylococcus aureus, Streptococcus mutans, and Pseudomonas aeruginosa) with a zone of inhibition ranging from 10.2 to 11.3 mm at the lowest tested concentration of 0.5 mg/ml. Altogether, our results highlight the unexplored potential of the naturally derived latex resin as a valuable and potent alternative for future therapeutics and drug discovery.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00532-0.

The tumor suppressor p53 plays an essential role in preserving genomic stability through DNA damage response (DDR) and apoptosis in mammalian systems. By comparison, the transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) is the main regulator of DDR in plants but has similar mechanisms to those occupied by p53 in humans. In this current study, we have designed and through computational characterization of a novel chimeric fusion protein composed of human p53 and the NAC domain of SOG1 from Arabidopsis thaliana, which was meant to increase the efficacy of DDR and apoptosis signaling. The fusion protein, a total of 336 amino acids and a molecular weight of 37.6 kDa, was modeled through protein-protein docking approaches with ClusPro and HDOCK, followed by molecular dynamics (MD) simulations of 100 ns to measure its stability, flexibility, and potential interactions with protein partners. The hybrid protein showed a favorable binding free energy with important regulatory partners MDM2 and BRCA1 (BRCT domain), and docked favorably with DNA (PDB ID: 1TUP), demonstrating that DNA-binding capability remained intact. This study proposes a new strategy for treating cancer and also expands the medicinal use of this study by describing, for the first time, the direct fusion of plant and animal protein, providing a new avenue for cross-kingdom therapeutic protein engineering.

Background: Breast cancer remains a leading cause of mortality among Indian women, with genetic and molecular factors playing crucial roles in its pathogenesis. Understanding the key genes and pathways involved can aid in developing targeted therapies and improving patient outcomes.

Methods: This study utilized publicly available gene expression datasets from the Gene Expression Omnibus (GEO), specifically GSE40206 and GSE89116, to identify differentially expressed genes (DEGs) in breast cancer among the Indian population. Data preprocessing, normalization, and statistical analysis were performed to identify significant DEGs. Pathway enrichment analysis, protein‒protein interaction (PPI) network construction, and survival analysis were conducted to identify key molecular mechanisms and potential therapeutic targets.

Results: Differential expression analysis revealed significant dysregulation of genes associated with immune response, lipid metabolism, and cell cycle regulation. Pathway enrichment highlighted PI3K-Akt and MAPK signalling and metabolic reprogramming. Protein-protein interaction analysis identified multiple hub genes, with ten showing significant or borderline associations with overall survival across age-stratified groups, indicating their potential utility as prognostic biomarkers.

Conclusion: This study provides valuable insights into the molecular landscape of breast cancer in the Indian population, highlighting key genes and pathways that may serve as therapeutic targets. Population-specific and age-stratified molecular studies are essential for advancing precision oncology and developing tailored treatment approaches for Indian breast cancer patients.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00581-z.

In contemporary area of medical research, repurposing of drugs has emerged as a promising strategy in drug discovery against viral infections in individual or in combination modes. The 3-chymotrypsin-like protease (3CL^pro) plays an essential role in mediating viral replication in the human body. It is key for developing potent and selective inhibitors for inhibiting viral replication. In this work, we have studied the possible efficacy of two popularly used repurposed drugs: Ivermectin and Doxycycline in their individual and combination modes as anti-viral agents. Density functional theory (DFT) was used to establish the chemical reactivity of the proposed drugs. Molecular electrostatic potential (MEP) and charge distribution analysis were used to check the antiviral effectivity. The study included the characteristics of the drug: 3CL^pro interactions through in-silico molecular docking and molecular dynamic (MD) simulation approaches through various thermodynamic parameters (E_pot, T, V, D, R_g, SASA energy) for identifying better reactiveness of both Ivermectin and Doxycycline in their individual and combination modes. Individually, Ivermectin showed a good binding affinity (-6.9 kcal/mol) over Doxycycline (-6.4 kcal/mol). In combination mode, Ivermectin + Doxycycline has showed a significant enhancement in the binding affinity (-7.4 kcal/mol). Our Insilco output has established that both individual and combination modes of prescribed repurposed drugs: Ivermectin and Doxycycline can be used as antiviral target towards the infections caused by 3CL^pro protease.

Free radicals contribute significantly to the development and progression of oxidative stress-related diseases. Essential oils from medicinal plants are rich in bioactive compounds with potential antioxidant activity. This study examines the potential of Dalbergiella welwitschii essential oils to prevent oxidative stress by their ability to scavenge free radicals. Essential oils were obtained from the leaves and stems using hydrodistillation, characterized by GC-MS and evaluated for antioxidant activity using the DPPH assay. Molecular Docking was used to assess interactions of the major compounds with oxidative-stress related enzymes (XOR, MO and NOX2) and ADMET studies were performed to predict pharmacokinetic behavior. Aristolone (32.3%) and 13-isopimaradiene (88.13%) were identified as the dominant compounds in the stem and leaf oils, respectively. Both oils exhibited good radical scavenging capacity, and low to moderate preliminary cytotoxicity. Molecular docking revealed strong binding affinities of 15-isopimaradiene to XOR (- 7.6 kcal/mol) and MPO (- 7.8 kcal/mol) comparable to reference drugs. ADMET analysis predicted good absorption and low toxicity suggesting drug-likeness potential. These findings indicate that Dalbergiella welwitschii essential oils may serve as promising natural antioxidants and scaffolds for drug discovery.

Opioids are potent analgesics and sedative compounds that acts primarily through opioid receptor (ORs) as µOR, δOR, κOR. Beyond their well-established roles in pain management, mood regulation, respiratory control, and ionic homeostasis, opioids are increasingly recognized for their modulating neuroinflammation via receptor-mediated pathways influencing glial activity and inflammatory signaling. The present study aimed to comparatively evaluate the pharmacokinetic profile and receptor-binding affinities of five natural opioids including morphine, codeine, noscapine, papaverine, and thebaine with a focus on their therapeutic efficacy, safety profile, and molecular targets implicated in opioid-mediated neuroinflammation to identify promising candidates for effective therapeutic intervention. Through integrative computational approaches including molecular docking, ADMET analysis, and network pharmacology, the study revealed favourable absorption and distribution for all compounds, though, morphine, noscapine, and papaverine exhibited potential toxicity. Differences in metabolism and excretion suggested variable pharmacokinetics. GO and KEGG analyses revealed involvement in calcium channel activity, neurotransmitter regulation, and dopaminergic synapse signaling. Protein Protein Interaction (PPI) network highlighted DRD2, OPRM1, and SIGMAR1 as key hub genes. Molecular docking showed noscapine, papaverine, and morphine had the highest affinity for µOR; morphine, codeine, and thebaine for δOR; and noscapine, papaverine, and thebaine for κOR. OPRM1 emerged as the primary target, followed by SIGMAR1 and DRD2. MD simulation suggest receptor's structural stability, supporting their potential to engage DRD2 in biologically relevant conformational states. The comparative analysis underscores the distinct pharmacological profiles of natural opioids and identifies potential molecular targets for developing safer, neuroinflammation-focused opioid therapies.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00584-w.

In the current study, a synthetic vinegar solvent (10% acetic acid) was employed to extract bioactive contents of Silybum marianum, and further in-vitro and in-silico methods were validated to authenticate its pharmacological behavior. The GC-MS profiling of Vinegar extract of Silybum marianum (VESM) revealed a diverse array of bioactives, including polyphenols, alkaloids, fatty acids, and sugar derivatives. According to the results of the DPPH assay, VESM exhibited strong antioxidant potential (67.6 ± 0.76%) that was nearly equivalent to the synthetic antioxidant BHA (65.1 ± 0.71%). The antimicrobial activity of VESM demonstrated higher inhibitory activity against Aspergillus fumigatus (36 ± 0.41 mm) and Staphylococcus aureus (27 ± 0.3 mm) as compared to fluconazole (21 ± 0.79) and gentamicin (19 ± 0.81), respectively. Furthermore, α-amylase inhibition assays revealed significant antidiabetic activity (61.31 ± 1.81%), compared to acarbose. In-silico molecular docking studies highlighted strong binding interactions between major polyphenols-particularly Phenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-methyl]-and target enzymes involved in microbial infection and glucose metabolism. The findings of this study clearly validate the pharmacological potential of VESM and support its application as a multifunctional, sustainable nutraceutical or herbal remedy for mitigating oxidative stress, microbial infections, and diabetes.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00553-3.

Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by MMUT deficiency, leading to severe neurological and metabolic complications. This study aimed to identify a core gene signature involved in MMA pathogenesis and to discover evolutionarily conserved microRNA (miRNA) regulators targeting MMUT by integrating human and mouse transcriptomic data. Microarray datasets for Homo sapiens (GSE120683) and Mus musculus (GSE41044, GSE118862) were analyzed using bioinformatic approaches. Differential gene expression (DEG) analysis was performed using the limma package (P < 0.05), and cross-species common genes were identified. Functional enrichment analyses (GO and KEGG) revealed affected pathways. miRNAs targeting MMUT were screened using multiMiR, followed by sequence-based conservation analysis. A total of 1,098 DEGs in human data and a core signature of 60 common genes in mouse models were identified. Functional analysis demonstrated that wound healing, kidney development, PI3K-Akt, and MAPK signaling pathways were commonly affected in both species. miRNA analysis revealed 17 evolutionarily conserved miRNAs with 100% sequence identity in both humans and mice. Notably, miR-181d-5p was identified to directly and specifically bind to the 3' UTR region of the MMUT mRNA through in silico validation. This finding highlights miR-181d-5p as a critical upstream regulator in the molecular pathogenesis of the disease. This study provides one of the first comprehensive analyses integrating transcriptional and post-transcriptional mechanisms in MMA. The identified conserved miRNA network, particularly the MMUT-specific miR-181d-5p, offers novel biomarkers for diagnosis and monitoring while presenting a promising target for RNA-based therapeutic interventions.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00591-x.