Integrated virtual screening and experimental validation identify dietary phytochemicals as PI3Kα inhibitors with antiproliferative activity.

Abstract

The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is a central regulator of cancer progression, with frequent activation of the PI3Kα catalytic subunit (p110α) in breast cancer. Here, an integrated in silico to experimental workflow was applied to systematically identify dietary phytochemicals capable of inhibiting PI3Kα and suppressing cancer cell proliferation. A curated PhytoHub library comprising 1966 food-derived compounds was screened by molecular docking against the PI3Kα catalytic domain, followed by isoform-specific enzymatic validation and cellular evaluation. Several flavonoids demonstrated strong PI3Kα inhibition at 30 μM, with jaceosidin and luteolin exhibiting the highest potency (IC₅₀ ≤ 0.1 and 0.76 μM, respectively), whereas anthocyanidins delphinidin and petunidin showed weaker activity. In MCF-7 breast cancer cells, myricetin, delphinidin, apigenin, and kaempferol produced the strongest antiproliferative effects (~55-65% inhibition; p < 0.05). These findings identify flavone-type scaffolds as potent PI3Kα inhibitors and highlight dietary flavonoids as promising functional food bioactives targeting oncogenic signaling.