Identification of phytomolecules as isoform and mutation specific PI3K-α inhibitor for protection against breast...

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Phosphoinositide 3-kinase alpha (PI3K-α) mutations are crucial in cancer development, especially in HR+/HER2- breast cancer.
• Mutant PI3K-α activates the PI3K/AKT/mTOR pathway, promoting tumor cell proliferation and survival.

Purpose of the Study:

• To identify natural compounds that can specifically inhibit mutant PI3K-α isoforms.
• To explore natural product-based therapeutic strategies for breast cancer treatment.

Main Methods:

• Generated an e-pharmacophore model using the Inavolisib drug (PDB:8EXV).
• Screened the Molport database of natural compounds using phase screening.
• Conducted molecular docking and molecular dynamics simulations on promising candidates.

Main Results:

• Identified seven potential PI3K-α inhibiting compounds through docking.
• Three compounds (STOCK1N-85097, STOCK1N-85998, STOCK1N-86060) exhibited significant stability and interaction with PI3K-α in simulations.
• These compounds showed favorable results in various computational analyses (RMSD, RMSF, Rg, SASA, PCA, FEL).

Conclusions:

• The identified natural compounds are potential inhibitors of mutant PI3K-α.
• These compounds may offer a therapeutic approach with potentially fewer side effects than conventional treatments.
• Further in vitro and in vivo validation is required to confirm efficacy and safety.