The discovery of a novel IκB kinase ß inhibitor based on pharmacophore modeling, virtual screening and biological evaluation.

ABSTRACT

Background: IκB kinase ß (IKKß) plays a pivotal role in the NF-κB signaling pathway and is considered a promising therapeutic target for various diseases. Materials & methods: The authors developed and validated a 3D pharmacophore model of IKKß inhibitors via the HypoGen algorithm in Discovery Studio 2019, then performed virtual screening, molecular docking and kinase assays to identify hit compounds from the ChemDiv database. The compound with the highest inhibitory activity was further evaluated in adjuvant-induced arthritis rat models. Results: Among the four hit compounds, Hit 4 had the highest IKKß inhibitory activity (IC50 = 30.4 ± 3.8), and it could significantly ameliorate joint inflammation and damage in vivo. Conclusion: The identified compound, Hit 4, can be optimized as a therapeutic agent for inflammatory diseases.

This research paper focuses on the development and validation of IκB kinase ß (IKKß) inhibitors. IKKß is a crucial enzyme that plays an important role in the NF-κB signaling pathway, which is involved in many diseases such as inflammatory diseases and cancers. The researchers used computer-aided drug design strategies to identify potential IKKß inhibitors. First, they used a model to screen a large database of chemical compounds. Then, they conducted further tests to pinpoint the ones that could effectively inhibit IKKß. Out of all the tested compounds, one referred to as 'Hit 4' showed the highest inhibitory activity. It was even able to significantly reduce joint inflammation and damage in rat models. Although many drugs targeting IKKß have been developed, none are commercially available yet due to issues with efficacy or safety. Therefore, the findings of this study are significant and could lead to the development of new effective therapeutic agents for inflammatory diseases.