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Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach

Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is...

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Autores principales: Veerappan, Karpagam, Natarajan, Sathishkumar, Ethiraj, Purushoth, Vetrivel, Umashankar, Samuel, Shila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130723/
https://www.ncbi.nlm.nih.gov/pubmed/27931154
http://dx.doi.org/10.1080/13880209.2016.1241809
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author Veerappan, Karpagam
Natarajan, Sathishkumar
Ethiraj, Purushoth
Vetrivel, Umashankar
Samuel, Shila
author_facet Veerappan, Karpagam
Natarajan, Sathishkumar
Ethiraj, Purushoth
Vetrivel, Umashankar
Samuel, Shila
author_sort Veerappan, Karpagam
collection PubMed
description Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions. Objective: This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta(1-42) (Aβ(1-42)) induced cytotoxicity and IKKβ activity, respectively. Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ(1-42) (IC(30) 10 μM) for 24 h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects. Results: Celastrol (1 μM) inhibited Aβ(1-42) (10 μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol. Discussion and conclusion: The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition.
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spelling pubmed-61307232018-09-27 Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach Veerappan, Karpagam Natarajan, Sathishkumar Ethiraj, Purushoth Vetrivel, Umashankar Samuel, Shila Pharm Biol Research Article Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions. Objective: This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta(1-42) (Aβ(1-42)) induced cytotoxicity and IKKβ activity, respectively. Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ(1-42) (IC(30) 10 μM) for 24 h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects. Results: Celastrol (1 μM) inhibited Aβ(1-42) (10 μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol. Discussion and conclusion: The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition. Taylor & Francis 2016-12-08 /pmc/articles/PMC6130723/ /pubmed/27931154 http://dx.doi.org/10.1080/13880209.2016.1241809 Text en © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Veerappan, Karpagam
Natarajan, Sathishkumar
Ethiraj, Purushoth
Vetrivel, Umashankar
Samuel, Shila
Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title_full Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title_fullStr Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title_full_unstemmed Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title_short Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach
title_sort inhibition of ikkβ by celastrol and its analogues – an in silico and in vitro approach
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130723/
https://www.ncbi.nlm.nih.gov/pubmed/27931154
http://dx.doi.org/10.1080/13880209.2016.1241809
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