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IKKβ inhibitor identification: a multi-filter driven novel scaffold.

Nagarajan S, Choo H, Cho YS, Shin KJ, Oh KS, Lee BH, Pae AN - BMC Bioinformatics (2010)

Bottom Line: Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size.This compound is novel among the known IKKβ inhibitors.Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuro-Medicine Center, Life/Health Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea. shanthi.bi@gmail.com

ABSTRACT

Background: Nuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKKα, IKKβ, and the regulatory domain NEMO, of which IKKβ is well understood in the canonical pathway. Therefore, the inhibition of IKKβ by drugs forms the molecular basis for anti-inflammatory drug research.

Results: The ligand- and structure-based virtual screening (VS) technique has been applied to identify IKKβ inhibitors from the ChemDiv database with 0.7 million compounds. Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size. Subsequently, recursive partitioning (RP) and docking filters were used to screen the pharmacophore hits. Finally, 29 compounds were selected for IKKβ enzyme inhibition assay to identify a novel small molecule inhibitor of IKKβ protein.

Conclusions: In the present investigation, we have applied various computational models sequentially to virtually screen the ChemDiv database, and identified a small molecule that has an IC50 value of 20.3μM. This compound is novel among the known IKKβ inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

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TR-FRET analysis of IKKβ phosphorylation inhibition by VH01 and Bayer-5a, a known compound used as a positive control.
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Figure 5: TR-FRET analysis of IKKβ phosphorylation inhibition by VH01 and Bayer-5a, a known compound used as a positive control.

Mentions: The IKKβ enzyme inhibition screening of 29 compounds revealed that two compounds have an inhibition effect of more than 20% at 10μM concentration (Fig. 4). The first compound, with 42.5% of inhibition, was found to have an IC50 value at 20.3 μM (Fig. 5). The positive control, Bayer-5a has been measured to have an IC50 value of 0.17 μM, which is 6.96 fold higher than that reported by Murata et al. [10] and could be due to differences in assay conditions. Based on the Bayer-5a screening result, it is expected that the hit compounds will be more potent in recombinant human IKKβ inhibition assays.


IKKβ inhibitor identification: a multi-filter driven novel scaffold.

Nagarajan S, Choo H, Cho YS, Shin KJ, Oh KS, Lee BH, Pae AN - BMC Bioinformatics (2010)

TR-FRET analysis of IKKβ phosphorylation inhibition by VH01 and Bayer-5a, a known compound used as a positive control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957683&req=5

Figure 5: TR-FRET analysis of IKKβ phosphorylation inhibition by VH01 and Bayer-5a, a known compound used as a positive control.
Mentions: The IKKβ enzyme inhibition screening of 29 compounds revealed that two compounds have an inhibition effect of more than 20% at 10μM concentration (Fig. 4). The first compound, with 42.5% of inhibition, was found to have an IC50 value at 20.3 μM (Fig. 5). The positive control, Bayer-5a has been measured to have an IC50 value of 0.17 μM, which is 6.96 fold higher than that reported by Murata et al. [10] and could be due to differences in assay conditions. Based on the Bayer-5a screening result, it is expected that the hit compounds will be more potent in recombinant human IKKβ inhibition assays.

Bottom Line: Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size.This compound is novel among the known IKKβ inhibitors.Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Neuro-Medicine Center, Life/Health Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea. shanthi.bi@gmail.com

ABSTRACT

Background: Nuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKKα, IKKβ, and the regulatory domain NEMO, of which IKKβ is well understood in the canonical pathway. Therefore, the inhibition of IKKβ by drugs forms the molecular basis for anti-inflammatory drug research.

Results: The ligand- and structure-based virtual screening (VS) technique has been applied to identify IKKβ inhibitors from the ChemDiv database with 0.7 million compounds. Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size. Subsequently, recursive partitioning (RP) and docking filters were used to screen the pharmacophore hits. Finally, 29 compounds were selected for IKKβ enzyme inhibition assay to identify a novel small molecule inhibitor of IKKβ protein.

Conclusions: In the present investigation, we have applied various computational models sequentially to virtually screen the ChemDiv database, and identified a small molecule that has an IC50 value of 20.3μM. This compound is novel among the known IKKβ inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

Show MeSH
Related in: MedlinePlus