1. Virtual screening against p50 NF-kappaB transcription factor for the identification of inhibitors of the NF-kappaB-DNA interaction and expression of NF-kappaB upregulated genes.
- Author
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Piccagli L, Fabbri E, Borgatti M, Bianchi N, Bezzerri V, Mancini I, Nicolis E, Dechecchi CM, Lampronti I, Cabrini G, and Gambari R
- Subjects
- Animals, Cell Line, DNA metabolism, Humans, Interleukin-8 genetics, Mice, Models, Molecular, NF-kappa B p50 Subunit genetics, Protein Binding, Protein Multimerization, RNA, Messenger genetics, Small Molecule Libraries chemistry, Transcription Factor RelB genetics, Gene Expression Regulation drug effects, NF-kappa B p50 Subunit antagonists & inhibitors, NF-kappa B p50 Subunit metabolism, Small Molecule Libraries pharmacology, Transcription Factor RelB antagonists & inhibitors, Transcription Factor RelB metabolism
- Abstract
Virtual screening against NF-kappaB 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-propenoate substructure and relevant druglike properties. Docking to p50 NF-kappaB was performed with a test set of six known inhibitors of NF-kappaB-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-kappaB-DNA interactions) and on biological functions dependent on NF-kappaB activity (inhibition of IL-8 gene expression in cystic fibrosis IB3-1 cells). We found that this in silico screening approach is suitable for the identification of low-molecular-weight compounds that inhibit NF-kappaB-DNA interactions and NF-kappaB-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-kappaB inhibitors.
- Published
- 2009
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