Novel IKKβ inhibitors discovery based on the co-crystal structure by using binding-conformation-based and ligand-based method

IκB kinase β (IKKβ), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKβ inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKβ. According to the chemical similarity, 162 reported IKKβ inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 μM. Compared to other models, our method considers the crystal structure of IKKβ for the first time.

Graphical abstractDocking conformations of two IKKβ inhibitors discovered based on the co-crystal structure by using binding conformation and ligand-based method from NCI and SPECS databases.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We adopted the co-crystal structure of IKKβ with its ligand for the first time. ► We developed five pharmacophore models based on cascade docking conformations. ► We combined the pharmacophore models and their separate shape queries. ► The virtual screening method has an excellent ability to discrete IKKβ inhibitors. ► Two lead compounds with IC50 values below 10 μM had been discovered.