Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206

Abstract

The AKT signaling pathway has been identified as an important target for cancer therapy. Among small-molecule inhibitors of AKT that have shown tremendous potential in inhibiting cancer, MK-2206 is a highly potent, selective and orally active allosteric inhibitor. Promising preclinical anticancer results have led to entry of MK-2206 into Phase I/II clinical trials. Despite such importance, the exact binding mechanism and the molecular interactions of MK-2206 with human AKT are not available. The current study investigated the exact binding mode and the molecular interactions of MK-2206 with human AKT isoforms using molecular docking and (un)binding simulation analyses. The study also involved the docking analyses of the structural analogs of MK-2206 to AKT1 and proposed one as better inhibitor. The Dock was used for docking simulations of MK-2206 into the allosteric site of AKT isoforms. The Ligplot+ was used for analyses of polar and hydrophobic interactions between AKT isoforms and the ligands. The MoMa-LigPath web server was used to simulate the ligand (un)binding from the binding site to the surface of the protein. In the docking and (un)binding simulation analyses of MK-2206 with human AKT1, the Trp-80 was the key residue and showed highest decrease in the solvent accessibility, highest number of hydrophobic interactions, and the most consistent involvement in all (un)binding simulation phases. The number of molecular interactions identified and calculated binding energies and dissociation constants from the co-complex structures of these isoforms, clearly explained the varying affinity of MK-2206 towards these isoforms. The (un)binding simulation analyses identified various additional residues which despite being away from the binding site, play important role in initial binding of the ligand. Thus, the docking and (un)binding simulation analyses of MK-2206 with AKT isoforms and its structure analogs will provide a suitable model for studying drug-protein interaction and will help in designing better drugs.

Development of a new model system to dissect isoform specific Akt signalling in adipocytes

“…Our data revealed that W80A conversion also renders both Akt1 and Akt2 insensitive to the MK-2206 inhibitor, a newer drug with enhanced affinity and improved target specificity [ 27 , 28 ]. Consistent with our data, recent molecular docking studies of Akt1 and MK-2206 identified W80 as a residue that mediates their interaction [ 43 ]. Importantly, whereas Akt1 W80A and Akt2 W80A mutants are both resistant to MK-2206, they are still dynamically regulated by insulin and their phosphorylation of downstream effectors is indistinguishable from that of their WT counterparts.…”

Foxc2 enhances proliferation and inhibits apoptosis through activating Akt/mTORC1 signaling pathway in mouse preadipocytes

“…MK2206 is an allosteric inhibitor of Akt, and it could bind to the Akt kinase domain, which is an allosteric site, resulting in a conformational change, and then block the ATP binding site. Moreover, MK2206 had been used as a selective allosteric inhibitor of Akt phosphorylation (27)(28)(29). We found that MK2206 signifi cantly blocked phosphorylation of Akt Ser473 and decreased the expression of the cyclin E and p27 ( P < 0.05) ( Fig.…”

Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer‐signaling PI3K/AKT/mTOR pathway

“…The AKT is a key player, whose activation and/or overexpression are commonly linked to resistance to chemotherapy or radiotherapy . The chemical compound inhibitors of AKT have huge potential for the treatment of various cancers …”