Oleuropein potently inhibits mammalian target of rapamycin: Possible involvement of tandem anomeric hyperconjugation-Michael reaction

Abstract

The reported anti-cancer properties of oleuropein combined with the recently elucidated role of mammalian target of rapamycin (mTOR) in various cancers, suggested the possibility that oleuropein inhibits mTOR. To validate this hypothesis, we docked oleuropein into the ATP-binding pocket of a close mTOR protein homolog, namely PI3K-γ. Apparently, oleuropein shared at least six critical binding interactions with the potent dual PIK3-γ/mTOR natural inhibitor quercetin. Subsequent experimental validation indicated that oleuropein indeed inhibited the enzymatic activity of mTOR with an IC 50 value of 0.905 μM. Lineweaver-Burk plot showed that oleuropein inhibits mTOR via mixed competitive/noncompetitive mechanism suggesting that inhibition is mediated, at least partially, by covalent bonding to mTOR binding pocket. Our findings strongly suggest that mTOR inhibition is at least one of the reasons for the reported anti-cancer properties of oleuropein.