title: Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques.
abstract: Various inflammatory stimuli that activate the nuclear factor kappa B (NF-κB) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-κB: the I kappa B kinase β (IKK-β). Therefore, IKK-β is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-β inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-β enzymatic activity in vitro and on NF-κB transactivation in intact cells. Compound 8 (2-(1-adamantyl)ethyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate) represents a novel chemical class of IKK-β inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-β ligands.
authors.affiliation: Department of Pharmaceutical Chemistry, Computer-Aided Molecular Design Group and Center of Molecular Biosciences Innsbruck-CMBI, Institute of Pharmacy, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Noha
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Nanang
authors.initials: N
authors.lastname: Fakhrudin
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
authors.forename: Olivia
authors.initials: O
authors.lastname: Schrammel
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C557270:2-(1-adamantyl)ethyl 4-((2,5-dihydroxyphenyl)methylamino)benzoate; D001565:Benzoates; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D051550:I-kappa B Kinase; D000218:Adamantane