Limits...
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.

Show MeSH

Related in: MedlinePlus

The Hypogen model composed of two ring aromatic (RAI and RAII), one hydrophobic and one hydrogen bond donor features.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2957683&req=5

Figure 1: The Hypogen model composed of two ring aromatic (RAI and RAII), one hydrophobic and one hydrogen bond donor features.

Mentions: Among the 10 pharmacophore models generated, model 1 was considered to be the best, because it has the lowest RMSD value (0.89Å) and a high correlation coefficient (r = 0.93) between the experimental and estimated activity data of the training set. The difference between the total and the hypothesis cost is 40.21. If the difference is 40-60 bits, then there is a 75-90% chance that this model can represent a true correlation of the data. Additionally, the difference between and fixed costs is more than 50 and the configuration cost is 16.17, which is less than the maximum threshold of 17. Cost analysis has confirmed that the statistical relevance of pharmacophore 1 being a reliable model in forecasting the activity precisely. Model 1 has four features, comprising an HD, two RA and an HyD (Fig. 1) and has been rigorously validated by estimating the activity of 136 compounds, whose experimental activity range span four orders of magnitude. The estimated activity is found to be fairly good and the correlation value (r) between the experimental and estimated value is 0.77. Detailed information about this pharmacophore is described elsewhere [7].


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)

The Hypogen model composed of two ring aromatic (RAI and RAII), one hydrophobic and one hydrogen bond donor features.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The Hypogen model composed of two ring aromatic (RAI and RAII), one hydrophobic and one hydrogen bond donor features.
Mentions: Among the 10 pharmacophore models generated, model 1 was considered to be the best, because it has the lowest RMSD value (0.89Å) and a high correlation coefficient (r = 0.93) between the experimental and estimated activity data of the training set. The difference between the total and the hypothesis cost is 40.21. If the difference is 40-60 bits, then there is a 75-90% chance that this model can represent a true correlation of the data. Additionally, the difference between and fixed costs is more than 50 and the configuration cost is 16.17, which is less than the maximum threshold of 17. Cost analysis has confirmed that the statistical relevance of pharmacophore 1 being a reliable model in forecasting the activity precisely. Model 1 has four features, comprising an HD, two RA and an HyD (Fig. 1) and has been rigorously validated by estimating the activity of 136 compounds, whose experimental activity range span four orders of magnitude. The estimated activity is found to be fairly good and the correlation value (r) between the experimental and estimated value is 0.77. Detailed information about this pharmacophore is described elsewhere [7].

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