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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2017-01-01
|
| Series: | Pharmaceutical Biology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/13880209.2016.1241809 |
| _version_ | 1818290499235086336 |
|---|---|
| author | Karpagam Veerappan Sathishkumar Natarajan Purushoth Ethiraj Umashankar Vetrivel Shila Samuel |
| author_facet | Karpagam Veerappan Sathishkumar Natarajan Purushoth Ethiraj Umashankar Vetrivel Shila Samuel |
| author_sort | Karpagam Veerappan |
| collection | DOAJ |
| 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 beta1-42 (Aβ1-42) induced cytotoxicity and IKKβ activity, respectively. Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ1-42 (IC30 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 Aβ1-42 (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. |
| first_indexed | 2024-12-13T02:29:08Z |
| format | Article |
| id | doaj.art-7b45252dab814984a321e4c87851f591 |
| institution | Directory Open Access Journal |
| issn | 1388-0209 1744-5116 |
| language | English |
| last_indexed | 2024-12-13T02:29:08Z |
| publishDate | 2017-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Pharmaceutical Biology |
| spelling | doaj.art-7b45252dab814984a321e4c87851f5912022-12-22T00:02:33ZengTaylor & Francis GroupPharmaceutical Biology1388-02091744-51162017-01-0155136837310.1080/13880209.2016.12418091241809Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approachKarpagam Veerappan0Sathishkumar Natarajan1Purushoth Ethiraj2Umashankar Vetrivel3Shila Samuel4VRR Institute of Biomedical Science (Affiliated to University of Madras)Sunchon National UniversitySRM Medical College Hospital and Research Centre, SRM UniversityCenter for Bioinformatics, Vision Research Foundation, Sankara NethralayaVRR Institute of Biomedical Science (Affiliated to University of Madras)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 beta1-42 (Aβ1-42) induced cytotoxicity and IKKβ activity, respectively. Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ1-42 (IC30 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 Aβ1-42 (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.http://dx.doi.org/10.1080/13880209.2016.1241809alzheimer’s diseaseneuroinflammationamyloid-βmolecular dockingadmet |
| spellingShingle | Karpagam Veerappan Sathishkumar Natarajan Purushoth Ethiraj Umashankar Vetrivel Shila Samuel Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach Pharmaceutical Biology alzheimer’s disease neuroinflammation amyloid-β molecular docking admet |
| 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 | alzheimer’s disease neuroinflammation amyloid-β molecular docking admet |
| url | http://dx.doi.org/10.1080/13880209.2016.1241809 |
| work_keys_str_mv | AT karpagamveerappan inhibitionofikkbbycelastrolanditsanaloguesaninsilicoandinvitroapproach AT sathishkumarnatarajan inhibitionofikkbbycelastrolanditsanaloguesaninsilicoandinvitroapproach AT purushothethiraj inhibitionofikkbbycelastrolanditsanaloguesaninsilicoandinvitroapproach AT umashankarvetrivel inhibitionofikkbbycelastrolanditsanaloguesaninsilicoandinvitroapproach AT shilasamuel inhibitionofikkbbycelastrolanditsanaloguesaninsilicoandinvitroapproach |