Identification of phytochemical as a dual inhibitor of PI3K and mTOR: a structure-based computational approach

Area of Science:

• Oncology
• Computational Chemistry
• Pharmacology

Background:

• Aberrations in the PI3K/AKT/mTOR pathway are common in cancer, including breast cancer.
• Dual targeting of PI3K and mTOR offers a strategy to effectively inhibit kinase-positive feedback loops.
• Identifying novel inhibitors for this pathway is crucial for developing new cancer therapies.

Purpose of the Study:

• To identify phytochemicals from the zinc 15 database that can inhibit both PI3K and mTOR.
• To evaluate the potential of these phytochemicals as dual inhibitors of the PI3K/AKT/mTOR pathway.
• To provide computational evidence for salvianolic acid A as a potential dual inhibitor.

Main Methods:

• Structure-based computational approaches including molecular docking, MM-GBSA, Qikprop, induced fit docking, and molecular dynamics (MD) simulations.
• Screening of phytochemicals from the zinc 15 database against PI3K (PDB 4FA6).
• Analysis of binding energies, ADME properties, and complex stability through MD simulations.

Main Results:

• Ten ligands were selected based on docking scores, with salvianolic acid C showing the highest score. Salvianolic acid A was also docked.
• All selected ligands exhibited binding energies greater than -30 kcal/mol, and predicted ADME properties indicated druggability.
• Molecular dynamics simulations revealed stable complexes between PI3K and specific ligands (ZINC000059728582, ZINC000257545754, ZINC000253532301, and salvianolic acid A), with ZINC000014690026 showing significant interaction with Val 882.

Conclusions:

• The study identified potential novel phytochemical inhibitors for the PI3K/AKT/mTOR pathway.
• Computational evidence supports salvianolic acid A as a promising candidate for dual inhibition of PI3K and mTOR.
• Further in vitro and in vivo experiments are warranted to validate these computational findings for breast cancer treatment.