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

PLOS ONE, Dec 2019

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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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. - 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)


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Mohd Rehan, Mohd A. Beg, Shadma Parveen, Ghazi A. Damanhouri, Galila F. Zaher. Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206, PLOS ONE, 2014, Volume 9, Issue 10, DOI: 10.1371/journal.pone.0109705