title: Discovery of novel potent nuclear factor kappa-B inhibitors (IKK-β) via extensive ligand-based modeling and virtual screening.
abstract: Inhibitor kappa-B kinase-beta (IKK-β) controls the activation of nuclear transcription factor kappa-B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti-inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK-β inhibitors to identify high-quality binding models. Subsequently, genetic algorithm-based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds. Three successful pharmacophores emerged in 2 optimal QSAR equations (r12175= 0.733, r12LOO= 0.52, F1 = 65.62, r12PRESSagainst 43 test inhibitors = 0.63 and r22175= 0.683, r22LOO= 0.52, F2 = 72.66, r22PRESSagainst 43 test inhibitors = 0.65). Two pharmacophores were merged in a single binding model. Receiver operating characteristic curve validation proved the excellent qualities of this model. The merged pharmacophore and the associated QSAR equations were applied to screen the National Cancer Institute list of compounds. Ten hits were found to exhibit potent anti-IKK-β bioactivity, out of which, one illustrates IC50 of 11.0nM.
authors.affiliation: Faculty of Pharmacy, Zarqa University, Zarqa, Jordan.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Al-Sha'er
authors.affiliation: Faculty of Pharmacy, Zarqa University, Zarqa, Jordan.
authors.forename: Inas S
authors.initials: IS
authors.lastname: Almazari
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan.
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve
chemical_list: D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase
keywords: IKK-β; IkBα; anti-inflammatory; anticancer; cyclooxygenase-2; human breast epithelial cells; ligand based analysis; serine peptidase