Hit identification of IKKβ natural product inhibitor

A structure-based molecular docking approach has been employed to discover novel IKKβ inhibitors from a natural product library of over 90,000 compounds. Preliminary screening of the 12 highest-scoring compounds using a luciferase reporter assay identified 4 promising candidates for further biological study. Among these, the benzoic acid derivative (1) showed the most promising activity at inhibiting IKKβ phosphorylation and TNF-α-induced NF-κB signaling in vitro.In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKKβ inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKKβ phosphorylation activity in vitro, and block IκBα protein degradation and subsequent NF-κB activation in human cells. Further in silico optimization of the compound is currently being conducted in order to generate more potent analogues for biological tests.The nuclear factor-κB (NF-κB) proteins are a small group of heterodimeric transcription factors that play an important role in regulating inflammatory, immune, and apoptotic responses [1-3]. NF-κB is ubiquitously present in the cytoplasm and its activity is normally suppressed by association with inhibitor IκB [4]. The intracellular NF-κB signaling cascade is initiated by a variety of inducers including proinflammatory cytokines TNF-α, IL-1 or endotoxins [5,6]. The aberrant activity to the NF-κB signaling pathway has been implicated in the development of a number of human diseases including cancer, auto-immune and chronic inflammatory conditions [3,7,8]. Therefore, inhibitors of the NF-κB signaling pathway could offer potential therapeutic value for the treatment of such diseases [9,10].The IκB kinase is a multi-component complex composed of two catalytic subunits, IKKα and IKKβ and a regulatory unit NF-κB essential modulator (NEMO) [11-13]. Although both catalytic units are able to phosphorylate IκB, IKKβ has been shown to play the dominant role in activating NF-κB signaling in