Targeting Breast Cancer with Polyalthia bullata Compounds: Insights from ADMET, Network Pharmacology, and Molecular Modeling

Breast cancer remains one of the most prevalent malignancies among women worldwide, underscoring the urgent need for safer and more effective therapeutic agents. This study investigates the potential anti-breast cancer properties of bioactive compounds derived from Polyalthia bullata King using an integrative computational and experimental approach. Sequential solvent extraction with solvents of varying polarities was employed to maximize the diversity of phytochemicals extracted from P. bullata. The major bioactive constituents were identified through ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOF/MS) analysis. The identified 130 compounds underwent ADMET-based screening to predict their drug-likeness and pharmacokinetic profiles. Drug-like 8 compounds were further explored through network pharmacology to predict potential breast cancer-related targets and involved signaling pathways. From this, 30,453 breast cancer-associated targets were retrieved from the GeneCards database, and 1,619 compound-related targets were identified via SwissTargetPrediction and SuperPred. Protein-protein interaction (PPI) network analysis revealed 646 overlapping targets. Subsequent Gene Ontology (GO) and KEGG pathway enrichment analyses highlighted the hsa05200: Pathways in cancer as a central mechanism, involving key proteins such as AKT1, GAPDH, and IL6. Molecular docking studies identified myricetin, bowdichione, and 4-methyl-1 H-benzogquinoline-2,5,10-trione as top candidates with strong binding affinities toward AKT1. These findings were further validated through molecular dynamics (MD) simulations, principal component analysis (PCA), free energy landscape (FEL) analysis, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations, all of which confirmed the stability and favorable binding of the compounds to the target protein. Overall, this study suggests that P. bullata-derived compounds, particularly myricetin, bowdichione, and 4-methyl-1 H-benzogquinoline-2,5,10-trione, hold promise as potential therapeutic agents against breast cancer and warrant further experimental investigation. Breast cancer remains one of the most prevalent malignancies among women worldwide, underscoring the urgent need for safer and more effective therapeutic agents. This study investigates the potential anti-breast cancer properties of bioactive compounds derived from Polyalthia bullata King using an integrative computational and experimental approach. Sequential solvent extraction with solvents of varying polarities was employed to maximize the diversity of phytochemicals extracted from P. bullata. The major bioactive constituents were identified through ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOF/MS) analysis. The identified compounds from the plant were subjected to ADMET analysis to predict their drug-likeness and pharmacokinetic profiles. Furthermore, the selected compounds from ADMET study were analyzed using network pharmacology to identify plausible signaling pathways and potential target proteins. These compounds were subsequently docked into the active site of the target protein to identify the lead candidate. The findings were further validated through molecular dynamics (MD) simulations, principal component analysis (PCA), free energy landscape (FEL) analysis, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations, all of which confirmed the stability and favorable binding of the compounds to the target protein. The identified 130 compounds underwent ADMET-based screening to predict their drug-likeness and pharmacokinetic profiles. Drug-like 8 compounds were further explored through network pharmacology to predict potential breast cancer-related targets and involved signaling pathways. From this, 30,453 breast cancer-associated targets were retrieved from the GeneCards database, and 1,619 compound-related targets were identified via SwissTargetPrediction and SuperPred. Protein-protein interaction (PPI) network analysis revealed 646 overlapping targets. Subsequent Gene Ontology (GO) and KEGG pathway enrichment analyses highlighted the hsa05200: Pathways in cancer as a central mechanism, involving key proteins such as AKT1, GAPDH, and IL6. Molecular docking studies identified myricetin, bowdichione, and 4-methyl-1H-benzogquinoline-2,5,10-trione as top candidates with strong binding affinities toward AKT1. Moreover, these complexes remained stable throughout the MD simulations and exhibited favorable binding affinities as determined by MM/GBSA analysis. This study suggests that P. bullata-derived compounds, particularly myricetin, bowdichione, and 4-methyl-1H-benzogquinoline-2,5,10-trione, hold promise as potential therapeutic agents against breast cancer and warrant further experimental investigation.