3D QSAR pharmacophore model based on diverse IKKβ inhibitors.
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.
Nagarajan
Shanthi
S
Center for Chemoinformatics Research, Life Sciences Division, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Ahmed
Asif
A
Choo
Hyunah
H
Cho
Yong Seo
YS
Oh
Kwang-Seok
KS
Lee
Byung Ho
BH
Shin
Kye Jung
KJ
Pae
Ae Nim
AN
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
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase