In Silico Exploration of Cordia Macleodii Derived Theaflavin as a Novel mTOR Inhibitor for Cancer Therapy

Abstract Theaflavin, a key polyphenolic compound, exhibits potent antioxidant, anti‐inflammatory, and anticancer activities. It neutralizes oxidative stress, inhibits pro‐inflammatory pathways, and targets oncogenic signaling molecules such as Bcl‐2, NF‐κB, and mTOR, leading to apoptosis and cell cycle arrest in cancer cells. Beyond oncology, theaflavins modulate gut microbiota, regulate glucose metabolism, and offer cardiovascular and neurological benefits, highlighting their therapeutic potential against cancer and chronic metabolic disorders. This study investigates theaflavin’s role as a strong mTOR inhibitor and apoptosis inducer through in silico approaches. Molecular docking against mTOR (PDB ID: 4FA6) identified high‐affinity candidates, which were further assessed for pharmacokinetic properties, drug‐likeness, and binding energy (Prime/MM‐GBSA). The top 20 hits underwent 3D‐QSAR modeling to predict inhibitory activity, while induced fit docking (IFD), immunohistochemistry, and Western blot analyses supported functional validation. Molecular dynamics simulations (MDS) over a 100‐ns trajectory evaluated the stability of the top four candidates. The most stable compound demonstrated strong structural integrity and a favorable safety profile, with a docking score correlating with an MM‐GBSA energy of −55.93 kcal/mol. ADMET analysis confirmed its promising pharmacokinetic and low‐toxicity characteristics, positioning it as a potential lead molecule for anticancer drug development.