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...

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Autores principales:	Mohd Rehan, Mohd A Beg, Shadma Parveen, Ghazi A Damanhouri, Galila F Zaher
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cdbecee0d83e46b68810817fb3f3c93b
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spelling	oai:doaj.org-article:cdbecee0d83e46b68810817fb3f3c93b2021-11-25T05:56:10ZComputational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206.1932-620310.1371/journal.pone.0109705https://doaj.org/article/cdbecee0d83e46b68810817fb3f3c93b2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0109705https://doaj.org/toc/1932-6203The 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.Mohd RehanMohd A BegShadma ParveenGhazi A DamanhouriGalila F ZaherPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e109705 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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.
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	article
author	Mohd Rehan Mohd A Beg Shadma Parveen Ghazi A Damanhouri Galila F Zaher
author_facet	Mohd Rehan Mohd A Beg Shadma Parveen Ghazi A Damanhouri Galila F Zaher
author_sort	Mohd Rehan
title	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_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_sort	computational insights into the inhibitory mechanism of human akt1 by an orally active inhibitor, mk-2206.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/cdbecee0d83e46b68810817fb3f3c93b
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Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206.

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