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

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

SUBMITTER: Noha SM 

PROVIDER: S-EPMC3013379 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature