Combination of pharmacophore model development and binding mode analyses: Identification of ligand features essential for IκB kinase-beta (IKKβ) inhibitors and virtual screening based on it

IκB kinase β (IKKβ) is an important anti-cancer target that plays crucial role in activating the transcription factor NF-κB in response to various inflammatory stimuli. In order to discover novel IKKβ inhibitors, a 3D chemical-feature-based QSAR pharmacophore model was established. A homology model of IKKβ enzyme was also developed to study the binding mode of IKKβ and its inhibitors. The two models were consistent in predicting the binding conformation of IKKβ inhibitor. Based on the virtual screening using the pharmacophore model, 16 compounds from SPECS database were selected after multiple filtrations for biological test. Two compounds with IC50 values lower than 10 μM were discovered.

Graphical abstractCombination of the pharmacophore and the homology model of IKKβ with its inhibitors shows that the type and spatial location of the chemical feature agree perfectly with the binding mode.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Models of IKKβ were constructed from both target-based and ligand-based method. ► Binding patterns of IKKβ with inhibitors were clarified by the constructed models. ► The IKKβ pharmacophore model is reliable for discovery of new inhibitors. ► Two compounds with IC50 lower than 10 μM were disclosed from virtual screening.