Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations

Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potent...

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Main Authors: Kannan, Srinivasaraghavan, Poulsen, Anders, Yang, Hai Yan, Ho, Melvyn, Ang, Shi Hua, Eldwin, Tan Sum Wai, Jeyaraj, Duraiswamy Athisayamani, Chennamaneni, Lohitha Rao, Liu, Boping, Hill, Jeffrey, Verma, Chandra Shekhar, Nacro, Kassoum
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2016
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Online Access:https://hdl.handle.net/10356/81961
http://hdl.handle.net/10220/41065
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-819612020-03-07T12:18:09Z Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations Kannan, Srinivasaraghavan Poulsen, Anders Yang, Hai Yan Ho, Melvyn Ang, Shi Hua Eldwin, Tan Sum Wai Jeyaraj, Duraiswamy Athisayamani Chennamaneni, Lohitha Rao Liu, Boping Hill, Jeffrey Verma, Chandra Shekhar Nacro, Kassoum School of Biological Sciences Eukaryotic initiation factor glutamic acid Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar to micromolar range. In the current work we model the inhibition of Mnk kinase activity by these inhibitors using various computational approaches. Combining homology modeling, docking, molecular dynamics simulations, and free energy calculations, we find that all compounds bind similarly to the active sites of both kinases with their imidazopyridine and imidazopyrazine cores anchored to the hinge regions of the kinases through hydrogen bonds. In addition, hydrogen bond interactions between the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131 (Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability of the bound conformations of the inhibitors. The computed binding free energies (ΔGPred) of these inhibitors are in accord with experimental bioactivity data (pIC50) with correlation coefficients (r2) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals energies and entropic effects appear to dominate the binding free energy (ΔGPred) for each Mnk–inhibitor complex studied. The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues. ASTAR (Agency for Sci., Tech. and Research, S’pore) 2016-08-04T09:22:55Z 2019-12-06T14:43:51Z 2016-08-04T09:22:55Z 2019-12-06T14:43:51Z 2015 Journal Article Kannan, S., Poulsen, A., Yang, H. Y., Ho, M., Ang, S. H., Eldwin, T. S. W., et al. (2015). Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations. Biochemistry, 54(1), 32-46. https://hdl.handle.net/10356/81961 http://hdl.handle.net/10220/41065 10.1021/bi501261j en Biochemistry © 2014 American Chemical Society. 15 p.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic Eukaryotic initiation factor
glutamic acid
spellingShingle Eukaryotic initiation factor
glutamic acid
Kannan, Srinivasaraghavan
Poulsen, Anders
Yang, Hai Yan
Ho, Melvyn
Ang, Shi Hua
Eldwin, Tan Sum Wai
Jeyaraj, Duraiswamy Athisayamani
Chennamaneni, Lohitha Rao
Liu, Boping
Hill, Jeffrey
Verma, Chandra Shekhar
Nacro, Kassoum
Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
description Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with a potency in the nanomolar to micromolar range. In the current work we model the inhibition of Mnk kinase activity by these inhibitors using various computational approaches. Combining homology modeling, docking, molecular dynamics simulations, and free energy calculations, we find that all compounds bind similarly to the active sites of both kinases with their imidazopyridine and imidazopyrazine cores anchored to the hinge regions of the kinases through hydrogen bonds. In addition, hydrogen bond interactions between the inhibitors and the catalytic Lys78 (Mnk1), Lys113 (Mnk2) and Ser131 (Mnk1), Ser166 (Mnk2) appear to be important for the potency and stability of the bound conformations of the inhibitors. The computed binding free energies (ΔGPred) of these inhibitors are in accord with experimental bioactivity data (pIC50) with correlation coefficients (r2) of 0.70 and 0.68 for Mnk1 and Mnk2 respectively. van der Waals energies and entropic effects appear to dominate the binding free energy (ΔGPred) for each Mnk–inhibitor complex studied. The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Kannan, Srinivasaraghavan
Poulsen, Anders
Yang, Hai Yan
Ho, Melvyn
Ang, Shi Hua
Eldwin, Tan Sum Wai
Jeyaraj, Duraiswamy Athisayamani
Chennamaneni, Lohitha Rao
Liu, Boping
Hill, Jeffrey
Verma, Chandra Shekhar
Nacro, Kassoum
format Article
author Kannan, Srinivasaraghavan
Poulsen, Anders
Yang, Hai Yan
Ho, Melvyn
Ang, Shi Hua
Eldwin, Tan Sum Wai
Jeyaraj, Duraiswamy Athisayamani
Chennamaneni, Lohitha Rao
Liu, Boping
Hill, Jeffrey
Verma, Chandra Shekhar
Nacro, Kassoum
author_sort Kannan, Srinivasaraghavan
title Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
title_short Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
title_full Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
title_fullStr Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
title_full_unstemmed Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations
title_sort probing the binding mechanism of mnk inhibitors by docking and molecular dynamics simulations
publishDate 2016
url https://hdl.handle.net/10356/81961
http://hdl.handle.net/10220/41065
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