Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques
| Autor: | Verena M. Dirsch, Atanas G. Atanasov, Judith M. Rollinger, Hermann Stuppner, Stefan M. Noha, Gerhard Wolber, Patrick Markt, Elke H. Heiss, Daniela Schuster, Nanang Fakhrudin, Olivia Schrammel |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Virtual screening
Models Molecular Molecular model Databases Factual Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Adamantane IκB kinase Ligands Biochemistry Benzoates Article Transactivation Drug Discovery Humans Computer Simulation Binding site Molecular Biology Protein Kinase Inhibitors ComputingMethodologies_COMPUTERGRAPHICS Binding Sites Pharmacophore Chemistry Organic Chemistry I-Kappa-B Kinase Shape-based screening Recombinant Proteins I-kappa B Kinase IKK-β Molecular Medicine Signal transduction I kappa B kinase β |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters |
| ISSN: | 1464-3405 0960-894X |
| Popis: | Graphical 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. |
| Databáze: | OpenAIRE |
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