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.