IKKβ inhibitor identification: a multi-filter driven novel scaffold

BMC Bioinformatics

Proceedings

Kwang-Seok Oh¹  Byung Ho Lee¹  Yong Seo Cho²  Ae Nim Pae²  Hyunah Choo²  Kye Jung Shin²  Shanthi Nagarajan³ 

[1] Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea;Neuro-Medicine Center, Life/Health Division, Korea Institute of Science and Technology, PO Box 131, 130-650, Cheongryang, Seoul, Republic of Korea;Neuro-Medicine Center, Life/Health Division, Korea Institute of Science and Technology, PO Box 131, 130-650, Cheongryang, Seoul, Republic of Korea;School of Science, Korea University of Science and Technology, 52 Eoeun dong, 305-333, Yuseong-guDaejeon, Republic of Korea;

关键词: Virtual Screening;    Pharmacophore Model;    Recursive Partitioning;    Matthews Correlation Coefficient;    Hinge Loop;   

DOI  :  10.1186/1471-2105-11-S7-S15

来源: Springer

【 摘 要 】

BackgroundNuclear 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.ResultsThe 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.ConclusionsIn 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 20.3μ M. This compound is novel among the known IKKβ inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

【 授权许可】

Unknown   
© Nagarajan et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.