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Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206
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 re...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201482/ https://www.ncbi.nlm.nih.gov/pubmed/25329478 http://dx.doi.org/10.1371/journal.pone.0109705 |
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author | Rehan, Mohd Beg, Mohd A. Parveen, Shadma Damanhouri, Ghazi A. Zaher, Galila F. |
author_facet | Rehan, Mohd Beg, Mohd A. Parveen, Shadma Damanhouri, Ghazi A. Zaher, Galila F. |
author_sort | Rehan, Mohd |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4201482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42014822014-10-21 Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 Rehan, Mohd Beg, Mohd A. Parveen, Shadma Damanhouri, Ghazi A. Zaher, Galila F. PLoS One Research Article 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. Public Library of Science 2014-10-17 /pmc/articles/PMC4201482/ /pubmed/25329478 http://dx.doi.org/10.1371/journal.pone.0109705 Text en © 2014 Rehan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rehan, Mohd Beg, Mohd A. Parveen, Shadma Damanhouri, Ghazi A. Zaher, Galila F. Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title | Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title_full | Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title_fullStr | Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title_full_unstemmed | Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title_short | Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206 |
title_sort | computational insights into the inhibitory mechanism of human akt1 by an orally active inhibitor, mk-2206 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201482/ https://www.ncbi.nlm.nih.gov/pubmed/25329478 http://dx.doi.org/10.1371/journal.pone.0109705 |
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