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This article is part of the supplement: Ninth International Conference on Bioinformatics (InCoB2010): Bioinformatics

Open Access Proceedings

IKKβ inhibitor identification: a multi-filter driven novel scaffold

Shanthi Nagarajan12, Hyunah Choo1, Yong Seo Cho1, Kye Jung Shin1, Kwang-Seok Oh3, Byung Ho Lee3 and Ae Nim Pae1*

Author Affiliations

1 Neuro-Medicine Center, Life/Health Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea

2 School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon 305-333, Republic of Korea

3 Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea

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BMC Bioinformatics 2010, 11(Suppl 7):S15  doi:10.1186/1471-2105-11-S7-S15

Published: 15 October 2010

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.