title: 3D QSAR pharmacophore model based on diverse IKKβ inhibitors.
abstract: The inhibitor kappaB kinase β (IKKβ) is a serine-threonine protein kinase that is critically involved in the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to various inflammatory stimuli. IKKβ-selective inhibitors could prove useful for the treatment of inflammatory diseases. In the absence of structural information, a ligand-based approach can serve as an alternative to the virtual screening of large databases. We have developed a 3D QSAR pharmacophore model based on 23 IKKβ inhibitors with 3 nM ≤ IC(50) ≤ 50000 nM. A four-feature pharmacophore containing a hydrophobic (Hy) feature, two ring aromatic (RA) features, and a hydrogen bond donor (D) feature was constructed. It yielded a correlation coefficient of 0.93 with experimentally determined activity data, and a correlation coefficient of 0.77 with training set activity data. The best hypothesis, Hypo 1, was validated by estimating the activities of 136 compounds in a test set. As well as the correlation analysis and test set activity estimation, a Fisher's validation test was conducted at the 95% confidence level. The pharmacophore model's specificity and selectivity were determined in an exhaustive enrichment study.
authors.affiliation: Center for Chemoinformatics Research, Life Sciences Division, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D020134:Catalytic Domain; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D016328:NF-kappa B / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase