A structural insight into the inhibitory mechanism of an orally active PI3K/mTOR dual inhibitor, PKI-179 using computational approaches

摘要: The PI3K/AKT/mTOR signaling pathway has been identified as an important target for cancer therapy. Attempts are increasingly made to design the inhibitors against key proteins of this anti-cancer PI3K/mTOR dual have proved more effective than only single protein targets. Recently discovered PKI-179, orally compound, is one such inhibitor targeting both PI3K and mTOR. This compound efficacious in vitro vivo. However, binding mechanisms molecular interactions PKI-179 with mTOR not yet available. current study investigated exact mode PI3Kγ using docking (un)binding simulation analyses. interacting residues their importance was ranked by loss accessible surface area, number residue, consistent appearance residue analysis. involved were Ala-805 Ile-2163 they lost maximum area due binding. In addition, which played a role drug but away from catalytic site also Finally, comparison respective sites done difference two proteins. Thus, pairs falling at similar location respect docked identified. striking similarity explains concomitant inhibition inhibitors. conclusion, analyses will provide suitable multi-target model studying drug-protein thus help designing novel drugs higher potency.