| Autor: |
Fernandes, Pedro A., Henriques, Elsa S., Pande, Vineet, Ramos, Maria. J., Maia, Ana R. R., Almeida, André A. S., Silva, Bruno F. B., Ribeiro, Carla M. S., Ribeiro, César F. B., Ribeiro, David S. M., Fonseca, Diana A. P., Cunha, Eva M. S., Maia, Filipe R. N. C., Pereira, Joana A. A., Pacheco, João P. G., Ferreira, Joaquim A. A. D., Matos, Liliana R. C., Pinto, Manuel A. B. P., Borges, Maria C. S., Magalhães, Paulo J. C. R. |
| Předmět: |
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| Zdroj: |
Theoretical Chemistry Accounts: Theory, Computation, & Modeling; May2005, Vol. 113 Issue 4, p197-204, 8p |
| Abstrakt: |
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 J2 (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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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