Psoralen derivatives as NF-kB/DNA interaction inhibitors: structural insight into the binding mode

NF-kB is a transcription factor involved in the control of a large number of normal cellular and organism processes, such as immune and inflammatory responses, cellular growth and apoptosis. The dysregulation of NF-kB is associated with many disease states such as AIDS and viral infections, arthritis and inflammatory diseases, cancer and also genetic disorders. In this way, targeting NF-kB could be of great interest in order to find new therapeutic agents, mainly anticancer and/or antiinflammatory compounds. Recently, psoralen derivatives able to inhibit NF-kB/DNA interactions and the related IL-8 gene expression were identified. Several novel psoralenes have been synthesized and evaluated through EMSA assay, in order to establish a Structure-Activity Relationship and to determine the structural determinant required to inhibit the NF-kB/DNA interaction. The binding mode of the compounds has been determined combining docking and 3D-QSAR studies: initially, 4 putative interaction sites have been identified through molecular docking approach. Then, the most plausible binding site has been selected by means of 3D-QSAR models.