In the current decade, the potential side effects caused by synthetic kinase domain inhibitors have paved the way for developing an alternative anti-breast cancer drug from botanical sources. Estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR) tyrosine kinase receptors play a key role in the activation of genomic and nongenomic related pathways of breast cancer progression. Paris polyphylla Smith (Melanthiaceae) is a rich source of steroidal saponins reported as an anti-breast cancer agent used among the local communities of Asian countries. In the present study, a total of 116 phytocompounds were characterized and identified from P. polyphylla rhizomes using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry tools. They were subjected to virtual screening, molecular docking, and molecular simulation analysis with these two breast cancer receptors. Among them, only three steroidal saponins, namely, diosgenin, pennogenin, and 7-ketodiosgenin acetate binding affinity with target receptors were on the higher side when compared with natural ligands. The highest affinity for the receptors ERα and EGFR tyrosine kinase was shown by 7-ketodiosgenin acetate with docking scores of −10.4 Kcal/mol and −11.2 Kcal/mol, respectively, followed by diosgenin and pennogenin. LigPlot + analysis revealed that the selected three steroidal saponins utilized a combination of hydrogen bonding and hydrophobic interactions to align themselves more efficiently in the ligand-binding pocket of the target receptors. Molecular simulation analysis revealed a stable interaction between the phytocompounds and the target receptors. Lipinski's rule confirmed pennogenin as the best phytocompound that could be used as a potential inhibitor against the two target breast cancer receptors (ERα and EGFR tyrosine kinase).

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