%0 Journal Article
%T Hit identification of IKK汕 natural product inhibitor
%A Chung-Hang Leung
%A Daniel Shiu-Hin Chan
%A Ying-Wei Li
%A Wang-Fun Fong
%A Dik-Lung Ma
%J BMC Pharmacology and Toxicology
%D 2013
%I BioMed Central
%R 10.1186/2050-6511-14-3
%X A structure-based molecular docking approach has been employed to discover novel IKK汕 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 IKK汕 phosphorylation and TNF-汐-induced NF-百B signaling in vitro.In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKK汕 inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKK汕 phosphorylation activity in vitro, and block I百B汐 protein degradation and subsequent NF-百B 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-百B (NF-百B) proteins are a small group of heterodimeric transcription factors that play an important role in regulating inflammatory, immune, and apoptotic responses [1-3]. NF-百B is ubiquitously present in the cytoplasm and its activity is normally suppressed by association with inhibitor I百B [4]. The intracellular NF-百B signaling cascade is initiated by a variety of inducers including proinflammatory cytokines TNF-汐, IL-1 or endotoxins [5,6]. The aberrant activity to the NF-百B 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-百B signaling pathway could offer potential therapeutic value for the treatment of such diseases [9,10].The I百B kinase is a multi-component complex composed of two catalytic subunits, IKK汐 and IKK汕 and a regulatory unit NF-百B essential modulator (NEMO) [11-13]. Although both catalytic units are able to phosphorylate I百B, IKK汕 has been shown to play the dominant role in activating NF-百B signaling in
%U http://www.biomedcentral.com/2050-6511/14/3