IKK<it>β </it>inhibitor identification: a multi-filter driven novel scaffold

• Main Authors: Oh Kwang-Seok, Shin Kye Jung, Cho Yong, Choo Hyunah, Nagarajan Shanthi, Lee Byung, Pae Ae
• Format: Article
• Language: English
• Published: BMC 2010-10-01
• Series: BMC Bioinformatics

<p>Abstract</p> <p>Background</p> <p>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, IKK<it>α</it>, IKK<it>β</it>, and the regulatory domain NEMO, of which IKK<it>β </it>is well understood in the canonical pathway. Therefore, the inhibition of IKK<it>β </it>by drugs forms the molecular basis for anti-inflammatory drug research.</p> <p>Results</p> <p>The ligand- and structure-based virtual screening (VS) technique has been applied to identify IKK<it>β </it>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 IKK<it>β </it>protein.</p> <p>Conclusions</p> <p>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 IC₅₀value of 20.3<it>μ</it>M. This compound is novel among the known IKK<it>β </it>inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.</p>