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Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206.

Rehan M, Beg MA, Parveen S, Damanhouri GA, Zaher GF - PLoS ONE (2014)

Bottom Line: 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 (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.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

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.

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Molecular docking analyses of MK-2206 to the allosteric site of human AKT1.Panel A: Human AKT1 is illustrated in cartoon representation and MK-2206 is in stick representation. The interacting residues are labeled and are shown as surface in different colors. Panel B: The possible aromatic stacking interaction of the amino acid residue, Trp-80 through its indole group with naphthyridin moiety of MK-2206 is shown.
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pone-0109705-g001: Molecular docking analyses of MK-2206 to the allosteric site of human AKT1.Panel A: Human AKT1 is illustrated in cartoon representation and MK-2206 is in stick representation. The interacting residues are labeled and are shown as surface in different colors. Panel B: The possible aromatic stacking interaction of the amino acid residue, Trp-80 through its indole group with naphthyridin moiety of MK-2206 is shown.

Mentions: The docking analyses of MK-2206 revealed that the compound packed against the residues Asn-53, Gln-59, Leu-78, Trp-80, Val-201, Leu-264, Val-270, and Tyr-272 of AKT1 and was stabilized by the hydrophobic interactions (Fig. 1A). The Dock score was negative with high absolute value and number of hydrophobic interactions that kept MK-2206 bound in the cavity was also reasonably high (25 interactions from 8 different residues, Table 1). All identified MK-2206 interacting residues of AKT1 with the loss in solvent accessibility and the total number of hydrophobic interactions are listed in Table 1. The higher the loss in solvent accessibility for a residue in the direction from unbound to the bound state, the more involved is the residue in the ligand binding [33]. The importance of AKT1 residues for MK-2206 binding were also ranked on the basis of loss in solvent accessibility (Table 1). The Trp-80 was identified as the key residue of AKT1 and was involved in the majority of hydrophobic interactions and showed highest decrease in its solvent accessibility after MK-2206 binding (approx. 77.85 Å2) as shown (Table 1). The Trp-80 was also the most common residue through all phases of MK-2206 (un)binding simulation (Fig. 2), demonstrating its importance in initial binding and finally bringing the drug into the active site of AKT1. Furthermore, Trp-80 also seemed to make aromatic stacking interactions between the indole group and naphthyridin moiety of MK-2206 (Fig. 1B). All the findings of Trp-80 as key interacting residue validates MK-2206 binding mode as these findings were consistent with a previous study [42] in which it is shown that the inhibition of AKT1 by Akti (an allosteric inhibitor of AKT) is critically dependent upon a solvent-exposed tryptophan residue (Trp-80) present in all three AKT isoforms and whose mutation to alanine yields an Akti-resistant kinase.


Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206.

Rehan M, Beg MA, Parveen S, Damanhouri GA, Zaher GF - PLoS ONE (2014)

Molecular docking analyses of MK-2206 to the allosteric site of human AKT1.Panel A: Human AKT1 is illustrated in cartoon representation and MK-2206 is in stick representation. The interacting residues are labeled and are shown as surface in different colors. Panel B: The possible aromatic stacking interaction of the amino acid residue, Trp-80 through its indole group with naphthyridin moiety of MK-2206 is shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4201482&req=5

pone-0109705-g001: Molecular docking analyses of MK-2206 to the allosteric site of human AKT1.Panel A: Human AKT1 is illustrated in cartoon representation and MK-2206 is in stick representation. The interacting residues are labeled and are shown as surface in different colors. Panel B: The possible aromatic stacking interaction of the amino acid residue, Trp-80 through its indole group with naphthyridin moiety of MK-2206 is shown.
Mentions: The docking analyses of MK-2206 revealed that the compound packed against the residues Asn-53, Gln-59, Leu-78, Trp-80, Val-201, Leu-264, Val-270, and Tyr-272 of AKT1 and was stabilized by the hydrophobic interactions (Fig. 1A). The Dock score was negative with high absolute value and number of hydrophobic interactions that kept MK-2206 bound in the cavity was also reasonably high (25 interactions from 8 different residues, Table 1). All identified MK-2206 interacting residues of AKT1 with the loss in solvent accessibility and the total number of hydrophobic interactions are listed in Table 1. The higher the loss in solvent accessibility for a residue in the direction from unbound to the bound state, the more involved is the residue in the ligand binding [33]. The importance of AKT1 residues for MK-2206 binding were also ranked on the basis of loss in solvent accessibility (Table 1). The Trp-80 was identified as the key residue of AKT1 and was involved in the majority of hydrophobic interactions and showed highest decrease in its solvent accessibility after MK-2206 binding (approx. 77.85 Å2) as shown (Table 1). The Trp-80 was also the most common residue through all phases of MK-2206 (un)binding simulation (Fig. 2), demonstrating its importance in initial binding and finally bringing the drug into the active site of AKT1. Furthermore, Trp-80 also seemed to make aromatic stacking interactions between the indole group and naphthyridin moiety of MK-2206 (Fig. 1B). All the findings of Trp-80 as key interacting residue validates MK-2206 binding mode as these findings were consistent with a previous study [42] in which it is shown that the inhibition of AKT1 by Akti (an allosteric inhibitor of AKT) is critically dependent upon a solvent-exposed tryptophan residue (Trp-80) present in all three AKT isoforms and whose mutation to alanine yields an Akti-resistant kinase.

Bottom Line: 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 (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.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

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.

Show MeSH
Related in: MedlinePlus