These findings highlight Langusei fruit as a promising natural source of safe, multi-target EGFR inhibitors with potential therapeutic relevance for NSCLC and highlight the need for in vitro and in vivo validation to confirm efficacy and selectivity.
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, with Epidermal Growth Factor Receptor (EGFR) mutations, particularly L858R, driving the progression and drug resistance of non-small cell lung cancer (NSCLC). Ficus minahassae (Langusei), an endemic species of North Sulawesi, contains diverse bioactive metabolites whose anticancer potential has not been explored. This study evaluated the potential of Langusei fruit metabolites as EGFR L858R inhibitors through an integrative in silico approach. Metabolites were identified via gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–high-resolution mass spectrometry (LC–HRMS). Target prediction was conducted using SwissTargetPrediction (probability > 0.5) and the Similarity Ensemble Approach (SEA) (MaxTC > 0.5), while NSCLC-related targets were retrieved from OMIM, GeneCards, Genpia2, DisGeNET, and cBioPortal. Network pharmacology and CytoHubba topology analyses were used to identify hub proteins, followed by ADMET profiling and molecular docking to assess binding affinity toward EGFR wild type and L858R mutant. A total of 170 metabolites were identified, dominated by fatty acyls, prenol lipids, and steroid derivatives. Integration of target prediction and disease databases revealed 355 overlapping proteins, among which seven hub proteins, including EGFR, STAT3, EP300, HSP90AA1, JUN, HIF1A, and ESR1, were identified as key regulators of oncogenic pathways. Molecular docking demonstrated that (Z)-1-(1,3-benzodioxol-5-yl)-3-methoxy-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one exhibited strong binding affinities to both EGFR wild type and L858R mutant and possessed a favorable ADMET profile comparable to Gefitinib and Osimertinib. These findings highlight Langusei fruit as a promising natural source of safe, multi-target EGFR inhibitors with potential therapeutic relevance for NSCLC. Further in vitro and in vivo validation is warranted to confirm efficacy and selectivity.
Non-small-cell lung cancer (NSCLC) remains the leading cause of lung cancer–related mortality, largely driven by aberrant activation of the epidermal growth factor receptor (EGFR). Despite the clinical success of EGFR tyrosine kinase inhibitors (TKIs), intrinsic and acquired resistance, coupled with safety concerns, highlight the need for novel, safer inhibitors. Natural products represent an underexplored source of structurally diverse bioactive compounds with favorable biocompatibility. In this study, a comprehensive in silico approach is used to evaluate phytochemicals from Adenium obesum as potential candidate EGFR-targeting compound. Initially, sixteen phytochemicals were first assessed for predicted antineoplastic activity using PASS. High-scoring molecules were docked against the EGFR kinase domain (PDB ID: 1M17), besides performed detailed protein–ligand interaction analysis, drug-likeness and ADMET profiling, toxicity prediction and 100-ns molecular dynamics (MD) simulations. PASS-based bioactivity prediction revealed strong anticancer potential among the sixteen screened compounds, with consistently high antineoplastic and antiproliferative activity probabilities (Pa > 0.79) and low inactivity scores, supporting their selection for subsequent docking, ADMET, and molecular dynamics analyses. Next, several phytochemicals exhibited strong docking affinities, with Cardenolide achieving the highest binding score (–9.9 kcal/mol) and forming stable interactions with key catalytic residues. A 100-ns MD simulation confirmed the structural stability, persistent binding, and dynamic integrity of the EGFR–Cardenolide complex under physiological conditions. Importantly, interaction mapping revealed that Cardenolide engages conserved and functionally critical regions of the EGFR kinase domain associated with catalytic activity and structural stability, supporting its mechanistic relevance as an ATP-competitive scaffold. Additionally, predicted pharmacokinetic and toxicity profiles further supported Cardenolide’s suitability as a drug-like candidate. Collectively, these results identify Cardenolide as a computationally prioritized candidate with favorable predicted EGFR-binding characteristics, structural stability, and physicochemical and toxicity profiles. However, as the present study is based entirely on computational analyses, these findings should be considered hypothesis-generating and do not establish EGFR inhibitory activity or therapeutic efficacy. Experimental validation, including biochemical kinase inhibition and cellular assays, is therefore required to determine the actual EGFR inhibitory potential and anticancer activity of Cardenolide. Nevertheless, the findings provide a rational basis for prioritizing Cardenolide for further experimental investigation and illustrate the potential of Adenium obesum phytochemicals as a source of candidate EGFR-targeting compounds for future NSCLC drug discovery.
Md. Naziur Rahman, Abu Yousuf Hossin, S. Talukder et al.· PLoS ONE· 0 citations
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
Background Breast cancer remains one of the leading causes of cancer-related mortality worldwide, and the emergence of drug resistance, systemic toxicity, and limited efficacy of current therapies highlight the need for safer and more effective treatment. Natural products have emerged as promising sources of multi-target anticancer agents.
A. cardamomum
has demonstrated preliminary anticancer potential, yet the bioactive constituents and their molecular mechanisms in breast cancer remain poorly elucidated. Methods This study integrated
in silico
approaches to investigate the therapeutic potential of
A. cardamomum
seed extract against breast cancer. LC–MS analysis identified phytochemical compounds, followed by network pharmacology to determine their potential targets and molecular pathways. Pharmacokinetic and toxicity predictions were assessed through ADMET and Lipinski’s rule of five analyses to evaluate drug-likeness and safety. Molecular docking and molecular dynamics (MD) simulations were conducted to evaluate binding affinity and structural stability of compounds with key oncogenic proteins. Results LC-MS profiling identified 22 distinct compounds in
A. cardamomum
seeds. ADMET and Lipinski analyses demonstrated that most compounds possessed high gastrointestinal absorption, favorable oral bioavailability, and low toxicity risk. Network pharmacology highlighting SRC, TNF-α, Caspase-3, and EGFR as central nodes in the protein-protein interaction network. Molecular docking identified compounds C17 and C20 as the most promising bioactives, showing strong binding affinities and interactions similar to control ligands. MD simulations confirmed their stable complexes, indicating conformational stability and robust ligand–protein interactions. Conclusion This study highlights the promising multi-target anticancer potential of
A. cardamomum
seeds. Compounds C17 and C20 were identified as lead candidates with strong and stable interactions with key breast cancer-related proteins and favorable pharmacokinetic properties. These results suggest that
A. cardamomum
could serve as a potential source for developing new plant-based therapies against breast cancer. Further
in vitro
and
in vivo
investigations are warranted to validate their efficacy and safety.
Dessy Arisanty, S. Khairani, K. Cuandra et al.· F1000Research· 0 citations
Background Laryngeal cancer, particularly laryngeal squamous cell carcinoma (LSCC), poses a significant threat to global health, especially within Asian populations. While Rabdosia Rubescens is known for its antitumor properties, the specific bioactive compounds and mechanisms underlying its activity against laryngeal carcinoma remain to be fully elucidated. Methods This study employed an integrated approach combining network pharmacology, molecular docking, and 500 ns molecular dynamics simulations to screen bioactive compounds from Rabdosia Rubescens. Key therapeutic targets were identified and validated using transcriptomic data from The Cancer Genome Atlas (TCGA). The most promising candidate was subsequently validated in vitro using cytotoxicity assays (TU177 and RK33 cell lines) and wound healing migration assays, alongside MMP9 knockdown models to confirm mechanistic specificity. Results Network pharmacology identified MMP9 as a critical therapeutic target, which was found to be significantly overexpressed in LSCC tissues. Virtual screening and MD simulations identified Cirsiliol as the most potent inhibitor among the tested phytochemicals, exhibiting a highly favorable binding free energy (ΔGbinding = −179.793 kJ/mol) and stable interactions with key residues (ALA189, HIS266, and LEU243). Experimental validation demonstrated that Cirsiliol induced dose-dependent growth inhibition with IC50 values of 31.59 μM in TU177 cells and 17.73 μM in RK33 cells. Furthermore, the compound significantly suppressed cell migration, mirroring the effects observed in MMP9-knockdown TU177 cells. Conclusion This study establishes Cirsiliol as a potent, specific inhibitor of MMP9 derived from Rabdosia Rubescens. By effectively targeting the MMP9 pathway, Cirsiliol suppresses tumor invasiveness and migration, highlighting its potential as a promising lead compound for the treatment of laryngeal cancer.
Xuefeng Wang, Guanying Ren, Yonggang Zhang et al.· Frontiers in Pharmacology· 0 citations
This study investigates the potential mechanisms through which the Rhubarb–Peach Kernel herb pair may exert effects in gastric cancer (GC) using network pharmacology and molecular docking approaches. Active compounds and their corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), with additional compound–target information obtained from DrugBank. Gastric cancer-related targets were collected from GeneCards, Online Mendelian Inheritance in Man (OMIM), the Therapeutic Target Database, and DrugBank. The overlapping targets were used to construct a compound–target–disease network and a protein–protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were subsequently performed. Nine candidate compounds were docked against 8 core targets to assess their predicted structural interactions. A total of 27 active compounds were identified, among which β-sitosterol, aloe-emodin, and hederagenin were identified as major candidate compounds. Tumor protein p53, caspase 3, and JUN were among the principal network targets. Enrichment analysis indicated that the overlapping targets were mainly associated with the p53 signaling pathway and other pathways involved in cancer-related processes, including apoptosis, cell survival, and inflammatory regulation. Molecular docking revealed differences in predicted binding scores among the 9 candidate compounds and 8 core targets, with several compound–target pairs showing comparatively lower docking energies. This in silico study suggests that the Rhubarb–Peach Kernel herb pair may act through multiple compounds, targets, and biological pathways relevant to GC. However, the identified targets are not necessarily specific to GC, and the molecular docking findings represent computational predictions rather than evidence of actual biological binding. These results should therefore be considered preliminary and hypothesis-generating, and further in vitro and in vivo studies are required to evaluate their biological and therapeutic relevance.
Non-Small Cell Lung Carcinoma (NSCLC) specifically is still one of
the top causes of cancer-related death globally. The multi-targeted mechanisms and lower toxicity
of natural products make them intriguing pharmacological candidates. Using a combination
of in vitro and in silico methods, the current study assessed the anticancer potential of the Ethanol
Extract of Carica papaya Linn. roots (EECP).
Phytochemical profiling and High-Performance Thin-Layer Chromatography
(HPTLC) analysis confirmed the presence of flavonoids, including rutin. The 2,2-diphenyl-1-
picrylhydrazyl (DPPH) assay was used to assess antioxidant activity. Cytotoxicity against Human
lung adenocarcinoma cell line (A549) and normal human lung fibroblast cell line (WI-38)
cells was evaluated, along with apoptosis via nuclear condensation, Deoxyribonucleic Acid
(DNA) fragmentation, and Reactive Oxygen Species (ROS) accumulation. Molecular docking
(SwissDock) and Absorption, Distribution, Metabolism, and Excretion (ADME) predictions
were performed to assess protein interactions, drug-likeness, and oral bioavailability.
EECP exhibited strong antioxidant activity (IC₅₀ = 4.07 μg/mL) and selective cytotoxicity toward A549 cells (IC₅₀ = 89.96 ± 0.24 μg/mL) with lower toxicity in WI-38 fibroblasts. Treatment induced significant ROS generation (213% at 300 μg/mL) and apoptotic changes. Docking studies revealed strong interactions of quercetin (–9.758 kcal/mol) and kaempferol (–9.353 kcal/mol) with oncogenic proteins, comparable to staurosporine (–10.439 kcal/mol). ADME predictions supported favorable bioavailability and drug-likeness.
Ethanolic extract demonstrated potent antioxidant activity (IC50 = 4.07 μg/mL) and selective
cytotoxicity against A549 cells (IC50 = 89.96±0.24 μg/mL), with comparatively lower
toxicity in WI-38 cells (IC50 = 75.83±0.34 μg/mL). Apoptosis was associated with nuclear condensation,
DNA fragmentation, and a 213% increase in ROS at 300 μg/mL. Docking studies
indicated strong binding of quercetin (-9.758 kcal/mol) and kaempferol (-9.353 kcal/mol) to oncogenic
proteins, comparable to that of staurosporine (-10.439 kcal/mol), mediated by hydrogen
bonds and hydrophobic interactions. Phenolic acids showed moderate interactions, and carpaine/
ergosta derivatives showed weaker interactions. ADME analyses revealed favourable oral
bioavailability and high gastrointestinal absorption for key flavonoids.
Ethanolic extract induces oxidative stress-mediated apoptosis and regulates key
signalling proteins, including Protein Kinase B (Akt) and tumor suppressor p53 (p53).
Overall, the EECP exhibits strong anticancer potential by inducing ROS-mediated
apoptosis and regulating Akt and p53, supporting further preclinical evaluation of C. papaya
Linn. root flavonoids for lung cancer.
Priyanka Bajpai, Phool Chandra, Om Prakash· Current Signal Transduction...· 0 citations
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