We present a series of new inhibitors of the association between nuclear factor kappa B (NF-
B) and the corresponding
B site in DNA. They were designed using the lead compound 15-deoxy-
12,14 -prostaglandin J
2 (PGJ2), which is a natural product with demonstrated inhibitory efficiency for this system. First, the binding mode of PGJ2 to NF-
B was unraveled by GOLD docking calculation. Subsequently, substitutions were made to PGJ2 to optimize its association with NF-
B. Care was taken not to strongly increase the reactivity of the new compounds, and to keep the overall shape, size and hydrophilicity of the lead compound, which should render them a similar bioavailability. Molecular mechanics calculations were performed to decide on the suitability of the substitutions, and to evaluate the energies of association with NF-
B. Density functional theory calculations were performed also to study the overall reactivity of the substituted drugs towards NF-
B. Important general conclusions were obtained, concerning the improvement of these natural inhibitors; namely, a set of rational methodologies were deduced to improve the association between the PGJ2 derivatives and NF-
B, and their efficiency demonstrated by generating a set of substituted complexes, some of them with a very much increased affinity for NF-
B, opening new doors to enlarge the therapeutic capabilities of this class of drugs.
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