Elucidation of HSP90AA1-directed therapeutic mechanisms of Semecarpus anacardium phytocomponents in brain tumors via network pharmacology, target interactome mapping, and molecular simulation analyses
Aug 2026· Network Modeling Analysis in Health Informatics and Bioinformatics· Vol 15· 0 citations· 75 references
TL;DR
This multi-layered computational investigation suggests that S. anacardium contains phytochemicals with computationally predicted interactions targeting HSP90AA1-associated pathways implicated in brain tumors, and identifies HSP90AA1 as a putative target for future experimental investigation for natural product-guided anti-brain tumor strategies.
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic efficacy due to tumor heterogeneity in conventional treatments. In the present study, an integrative, network pharmacology approach was employed to elucidate the multi-target mechanism of action of phytochemicals derived from Glossocardia bosvallia against NSCLC. Among 38 phytocompounds identified, 31 compounds that satisfied pharmacokinetic properties were selected for subsequent analysis. Ligand-based target prediction identified 429 potential protein targets, which are integrated with the top 250 differentially expressed genes obtained from the GSE33532 dataset. Intersection analysis identified eight therapeutic targets: PTGES, SRD5A1, CDK1, KIF11, TOP2A, CDC45, MB, and CHEK1. Protein-protein interaction and enrichment analyses demonstrated that these targets are predominantly involved in cell cycle regulation, mitotic cell cycle, and DNA replication pathways. Gene expression analysis demonstrated significant overexpression of the prioritized targets in NSCLC tissues, while survival analysis identified CHEK1 as the gene significantly associated with survival (p < 0.05). Molecular docking identified TOP2A_quinic acid as the most favorable complex, exhibiting a binding affinity of -12.27 kcal/mol, KIF11_linoleic acid as -12.10 kcal/mol and CHEK1_2,3-dihydro-3,5-dihydroxy-6-methyl-4h-pyran-4-one as -6.75 kcal/mol, which was further validated by dynamic simulations, principal component analysis based free energy landscape, and DSSP analysis, confirming the stability of the protein. This integrative framework provides a robust strategy for identifying biologically relevant and therapeutically actionable targets supporting the potential of G. bosvallia-derived phytochemicals as promising candidates for NSCLC.
S. Kulandhaivel, A. Stalin, Pandiyan Muthuramalingam et al.· Computational biology and ch...· 0 citations
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder lacking effective disease-modifying therapies. Astragalus membranaceus (AM) has shown potential neuroprotective effects, but its underlying mechanisms remain incompletely understood. In this study, a meta-analysis, network pharmacology, molecular simulation, and experimental validation were integrated to investigate the therapeutic potential of AM in AD. Meta-analysis of three randomized controlled trials showed that AM significantly improved Clinical Dementia Rating-Sum of Boxes scores, whereas no significant differences were observed for MMSE, memory-related outcomes, or SNSB-D. Network pharmacology identified 350 overlapping targets between AM and AD, with enrichment in pathways related to PI3K-Akt signaling and neural ligand-receptor interactions. HSP90AA1, PIK3CA, and ESR1 were identified as hub targets. Molecular docking predicted stable binding of astragaloside VII to the ATP-binding pocket of HSP90AA1 (-8.9 kcal/mol), which was further supported by molecular dynamics simulation and MM/PBSA analysis (-63.13 ± 4.82 kcal/mol). In Aβ-induced SH-SY5Y cells, astragaloside VII improved cell viability, reduced inflammatory cytokine production and the Aβ42/Aβ40 ratio, restored mitochondrial membrane potential, decreased reactive oxygen species accumulation, alleviated Tau hyperphosphorylation, and increased PSD95 expression. These effects were markedly attenuated following HSP90AA1 knockdown. Collectively, these findings suggest that AM may exert neuroprotective effects through HSP90AA1-associated regulation of multiple AD-related pathological processes and provide preliminary evidence supporting further mechanistic and translational studies.
Min Xie, Xiaoli Niu, Lin Shi· Neuroscience· 0 citations
Findings highlight Withaferin A as a promising natural inhibitor of UBE2J1 and provide a foundation for future experimental validation aimed at developing targeted therapies against ovarian cancer.
Zujaja Rehman, Ejaz Rasul, Wisha Asif et al.· In Silico Pharmacology· 0 citations
Melanoma is an aggressive skin cancer with frequent therapeutic resistance, highlighting the need for multi-target discovery strategies. In this study, an integrative workflow combining LC–HRMS metabolite profiling, network pharmacology, structure-based modeling, and phenotypic evaluation was applied to explore the anti-melanoma potential of Zanthoxylum acanthopodium ethanol extract (ZAE). LC–HRMS analysis followed by ADMET-guided screening prioritized 12 candidate metabolites representing diverse structural classes. Integration of transcriptomic datasets, GeneCards targets, and compound-based predictions identified eight consensus genes, with poly(ADP-ribose) polymerase 1 (PARP1) emerging as the top hub within the protein–protein interaction network. Functional enrichment analysis highlighted pathways associated with DNA damage response and apoptosis-related signaling. Molecular docking against the PARP1 catalytic domain suggested favorable binding profiles for several prioritized metabolites, and molecular dynamics simulation supported stable interaction behavior under dynamic conditions. In vitro anticancer evaluation in A375 melanoma cells demonstrated concentration-dependent reduction in viability (IC₅₀ = 128.03 ± 10.17 μg/mL, 24 h) accompanied by apoptosis-associated nuclear alterations. Overall, this study provides a chemically informed, systems-level framework indicating that ZAE-derived metabolites may influence melanoma cell survival through PARP1-centered stress and apoptosis signaling, offering a foundation for future target validation and structure-guided optimization.
Linda Chiuman, Dewi Purnama, C. Ginting et al.· Journal of Multidisciplinary...· 0 citations
Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited therapies. We explored the anti-HCC mechanisms of Zanthoxylum nitidum (Roxb.) DC. via network pharmacology, bioinformatics and molecular docking. We identified its active components, targets and HCC-related key genes by differential expression analysis. Enrichment analysis showed these targets act in HCC-related pathways like alcoholic liver disease and the PPAR signalling pathway. Machine learning screened 5 characteristic genes (ESR1, CCNA2, CYP2B6, CHRM2, IL10), among which ESR1 and CCNA2 correlate with patient prognosis. These genes regulate tumour microenvironment and show epigenetic variations in methylation and copy number. Molecular docking confirmed stable binding between plant components and core targets. This study first reveals the multi-target anti-HCC mechanisms of Z. nitidum, offering evidence for its clinical use. Follow-up experiments are needed to validate our findings.
Rongjie Zhang, Ge Zhou, Jinhai Luo et al.· Artificial Cells Nanomedicin...· 0 citations
The most terrifying cardiac complication of Trypanosoma cruzi infection is Chronic Chagasic Cardiomyopathy (CCC), which is the complication that occurs in about one-third of the infected individuals and is one of the major causes of non-ischemic heart failure in Latin America. Although fairly disease-burdening, the molecular pathways of CCC immunopathology are not fully studied, and disease-modifying therapy is currently lacking. This study used an integrative computational strategy involving RNA-seq transcriptomics, protein-protein interaction (PPI) network analysis, gene ontology and KEGG pathway enrichment, molecular docking, ADMET profiling, and molecular dynamics simulations to define the host immune transcriptional environment of CCC and determine which phytochemicals may regulate its major regulation targets. RNA-seq analysis of severe CCC cardiac tissue compared to healthy controls (GEO: GSE191081) found 2,973 significantly differentially expressed genes (DEGs), 2,239 of which were upregulated, and 734 of which were downregulated. The analysis of functional enrichment showed that the upregulated genes were most linked to T cell activation, antigen receptor-mediated signaling, cytokine production, and MHC complex assembly, whereas downregulated genes were enriched in potassium ion transport, sarcoplasmic reticulum functioning and cardiomyocyte survival pathways. Multi-algorithm hub gene analysis with cytoHubba on PPI networks revealed 5 core regulatory genes, including CD4, PTPRC, CD8A, IFNG and FCGR3A, that were invariably within the top five network topologies of all five topological models (Degree, MCC, MNC, Closeness, and EPC). Among them, CD8A (PDB: 1CD8) and PTPRC (PDB: 1YGR) were chosen to be screened virtually against 110 drug-like phytochemical compounds of Schinus molle downloaded in the IMPPAT database with and without structure. The highest-ranking compound found in molecular docking relative targeting PTPRC (−7.70 kcal/mol) and CD8A (−6.94 kcal/mol), IMPHY006486, was also found to have strong binding affinities with diverse interactions with the essential active site residues, such as Ser928, Gln882, Phe890 (PTPRC) and Thr30, Phe48, Tyr51 (CD8A). Favorable pharmacokinetic properties of the lead compounds including high intestinal absorption, lack of risk of CYP-mediateddrug interaction and negative AMES mutagenicity were confirmed by ADMET profiling. All four protein-ligand complexes were found to be structurally stable at 100 nanoseconds in molecular dynamics simulations, with moderate backbone RMSD (1.52–2.82 A), maintained components of secondary structure, and maintained protein-ligand interaction fractions over the trajectories. Such results indicate that IMPHY006486, IMPHY004111, and IMPHY003082 emerged as computationally prioritized candidates for further experimental evaluation as potential modulators of CD8A and PTPRC. They should be validated experimentally to demonstrate their therapeutic potential. This is a systems-level and structure-based study that points out important immune hubs in the development of CCC pathogenesis and shows how combined transcriptomics and molecular modeling can identify immunomodulatory candidates faster in the context of Chagas heart disease.
Sultan K. Al-Umairi, Sana Abdul Ghaffar, Farah Shahid et al.· Records of Natural Products· 0 citations