Identification of phytomolecules as isoform and mutation specific PI3K-α inhibitor for protection against breast cancer using e-pharmacophore modeling and molecular dynamics simulations

PI3K-α mutation plays a critical role in cancer development, notably in breast cancer, particularly within HR + /HER2- subtypes. These mutations drive tumor growth and survival by activating the PI3K/AKT/mTOR pathway, which is essential for cell proliferation and survival. Our research aimed to identify natural compounds that can inhibit mutant and specific isoforms of PI3K-α to prevent tumor progression. e-Pharmacophore model was generated using Receptor-Ligand complex using the Inavolisib drug (PDB:8EXV) and phase screening was performed using the Molport database of natural compounds. Through molecular docking studies we identified seven promising compounds for further molecular dynamics simulations. Among these, three compounds—STOCK1N-85097, STOCK1N-85998, and STOCK1N-86060—showed significant stability and interaction with PI3K-α. These compounds demonstrated favorable results in several parameters, including RMSD, RMSF, Rg, SASA, PCA, FEL, and total energy evaluations. Therefore, these compounds are projected to function as PI3K-α inhibitors and because of its natural origin it can possess fewer side effects than the conventional medicine, which should be validated by proper in vivo and in vitro models.