Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Noha, Stefan M.^1,2  Atanasov, Atanas G.⁴  Schuster, Daniela^1,2,6  Markt, Patrick^1,2,6  Fakhrudin, Nanang⁴  Heiss, Elke H.⁴  Schrammel, Olivia⁴  Rollinger, Judith M.^2,3  Stuppner, Hermann^2,3  Dirsch, Verena M.⁴  Wolber, Gerhard^1,2,5 

[1] Univ Innsbruck, Inst Pharm, Dept Pharmaceut Chem, Comp Aided Mol Design Grp, A-6020 Innsbruck, Austria

[2] Univ Innsbruck, Ctr Mol Biosci Innsbruck CMBI, A-6020 Innsbruck, Austria

[3] Univ Innsbruck, Inst Pharm, Dept Pharmacognosy, A-6020 Innsbruck, Austria

[4] Univ Vienna, Dept Pharmacognosy, A-1090 Vienna, Austria

[5] Free Univ Berlin, Inst Pharm, D-14194 Berlin, Germany

[6] Inte Ligand Softwareentwicklung & Consulting GmbH, A-1070 Vienna, Austria

关键词: I kappa B kinase beta;    IKK-beta;    Virtual screening;    Pharmacophore;    Shape-based screening;   

DOI  :  10.1016/j.bmcl.2010.10.051

来源: Elsevier

【 摘 要 】

Various inflammatory stimuli that activate the nuclear factor kappa B (NF-kappa B) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-kappa B: the I kappa beta Bkinase beta (IKK-beta). Therefore, IKK-beta is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-beta 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-beta enzymatic activity in vitro and on NF-kappa B transactivation in intact cells. Compound 8 (2-(1-adamantyl) ethyl 4-[(2,5-dihydroxyphenyl) methylamino] benzoate) represents a novel chemical class of IKK-beta inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-beta ligands. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free