Virtual Screening against p50 NF-[kappa]B Transcription Factor for the Identification of Inhibitors of the NF-[kappa]B-DNA Interaction and Expression of NF-[kappa]B Upregulated Genes

Virtual screening against NF-[kappa]B p50 using docking simulations was applied by starting from a three-dimensional (3D) database containing more than 4.6 million commercially available structures. This database was filtered by specifying a subset of commercially available compounds sharing a (2E,Z)-3-(2-hydroxyphenyl)-2-prop enoate substructure and relevant druglike properties. Docking to p50 NF-[kappa]B was performed with a test set of six known inhibitors of NF-[kappa]B-DNA interactions. In agreement with docking results, the highest-scored compound displayed a high level of inhibitory activity in electrophoretic mobility shift assay (EMSA) experiments (inhibition of NF-[kappa]B-DNA interactions) and on biological functions dependent on NF-[kappa]B activity (inhibition of IL-8 gene expression in cystic fibrosis IB3-1 cells). We found that this insilico screening approach is suitable for the identification of low-molecular-weight compounds that inhibit NF-[kappa]B-DNA interactions and NF-[kappa]B-dependent functions. Information deduced from the discovery of the new lead compound and its binding mode could result in further lead optimization resulting in more potent NF-[kappa]B inhibitors. Inhibiting interactions: We applied a combined insilico screening and experimental approach to discover inhibitors of the NF-[kappa]B-DNA interaction and dependent functions. The studies were performed by starting from a large commercial database of small molecules. Our strategy led to the identification of a new lead compound with an IC sub(50) value 100-fold higher than that of the reference structure.