title: IKKβ inhibitor identification: a multi-filter driven novel scaffold.
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.
authors.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
authors.forename: Shanthi
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003663:Decision Trees; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase