Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206
MK-2206. PLoS ONE 9(10): e109705. doi:10.1371/journal.pone.0109705
Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206
Mohd Rehan 0
Mohd A. Beg 0
Shadma Parveen 0
Ghazi A. Damanhouri 0
Galila F. Zaher 0
Mohammad Saleem, Hormel Institute, University of Minnesota, United States of America
0 1 King Fahd Medical Research Center, King Abdulaziz University , Jeddah , Kingdom of Saudi Arabia, 2 Bareilly College, M. J. P. Rohilkhand University , Bareilly, Uttar Pradesh , India , 3 Department of Haematology, Faculty of Medicine, King Abdulaziz University , Jeddah, Kingdom of Saudi Arabia
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.
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Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the Supporting
Information files.
Funding: The authors have no funding or support to report.
Competing Interests: The authors have declared that no competing interests exist.
The PI3K/AKT/mTOR signaling pathway is an important
pathway for normal cellular functions in the human body and is
the most commonly dysregulated pathway in cancer [1,2]. The
AKT is one of the key proteins of this pathway belonging to the
serine/threonine AGC protein kinase family and is also known as
Protein Kinase B (PKB). The human AKT is found in three
isoforms AKT1, 2, and 3, also known as PKB-a, -b and -c and
these isoforms are highly homologous multi-domain proteins
possessing both common and distinct cellular functions [3,4]. The
AKT is involved in several functions in the body such as
metabolism, growth, proliferation, differentiation, and survival of
the cells [5,6]. Conversely in regards to cancer, the constant
activation and/or over-expression of AKT frequently contributes
to the resistance to cancer chemotherapy or radiotherapy [7,8].
Recently, in vitro and in vivo studies with small molecule
inhibitors of the AKT have been successful in attenuating
chemotherapeutic resistance when combined with the standard
chemotherapy [9,10]. Therefore, specific inhibition of AKT
activity may be a good alternative approach to treat cancer and
increase the efficacy of chemotherapy. In this regard, significant
efforts have been made to generate chemical compounds designed
specifically to target AKT or other targets in the AKT signaling
pathway and some of these compounds are in clinical trials for
cancer treatment [2]. The majority of known AKT inhibitors are
ATP competitive and have poor specificity against other closely
related kinases. The increasing attention for AKT specific
inhibitors or even AKT-isoform specific inhibitors led to the
discovery of allosteric AKT inhibitors [1113]. One such
compound, MK-2206 (IUPAC name:
8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3one), is a highly potent, selective, and orally active allosteric
inhibitor of AKT which has been recently identified [1416] and is
effectiv (...truncated)