In this study we intended to perform insilico and invitro analysis of  naturally derived flavonoid , hesperetin as a promising  mTOR (mammalian target of rapamycin) inhibitor .This study features insilico screening of natural compound hesperetin against mTOR FKBP12 domain by using Schrodinger glide based virtual screening and further molecular dynamics simulation was done to infer the stability of complex formation. mTOR co-crystallized with P2X (a known inhibitor of mTOR) (PDB ID: 4JT5) was used for reference guided docking protocol. Then in vitro analysis applying hesperetin for cell viability followed by protein expressions in PA-1 ovarian and MCF-7 breast cancer cell lines were performed dose dependently. Insilico molecular docking and dynamic studies with mTOR protein revealed that hesperetin was found to be a potent compound that could inhibit the FKBP12 domain of mTOR. The In vitro studies with hesperetin on PA-1 and MCF-7 cancer cells, found that hesperetin inhibits mTOR and its downstream molecule pS6-70k, dose-dependently. To the best of our knowledge this is the first study that brings up the scientific evidence for the efficacy of hesperetin in inhibiting mTOR with a similar docking score to the native ligand and also in a dose dependent manner in PA-1 human ovarian cancer cells and MCF-7 breast cancer cells.This study might facilitate thorough and deeper insights in inhibiting mTOR with natural flavonoid hesperetin as an anticancer agent with further studies in near future.

Keywords :Hesperetin, mTOR, FKBP12, Docking, Molecular dynamics,  PA-1, MCF-7, pS6-70k Anticancer.