New designs for inhibitors of the NF-kappa B: DNA binding

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Fernandes, PA (Author) FCUP; Maia, ARR (Author) Other; Almeida, AAS (Author) Other; Silva, BFB (Author) Other; Ribeiro, CMS (Author) Other; Ribeiro, CFB (Author) Other; Ribeiro, DSM (Author) Other; Fonseca, DAP (Author) Other; Henriques, ES (Author) Other; Cunha, EMS (Author) Other; Maia, FRNC (Author) Other; Pereira, JAA (Author) Other; Pacheco, JPG (Author) Other; Ferreira, JAAD (Author) Other; Matos, LRC (Author) Other; Pinto, MABP (Author) Other; Borges, MCS (Author) Other; Magalhaes, PJCR (Author) Other; Teixeira, PFRD (Author) Other; Veloso, PNBC (Author) Other; Ferreira, RJF (Author) Other; Gomes, SS (Author) Other; Barros, TF (Author) Other; Selao, TSJT (Author) Other; Pande, V (Author) Other; Fernandes, VMMC (Author) Other; Ramos, MJ (Author) FCUP

Journal

Title: Theoretical Chemistry Accounts

Vol. 113

Pages: 197-204

ISSN: 1432-881X

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 2 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-000-3R7

DOI: 10.1007/s00214-005-0628-1

Abstract (EN): We present a series of new inhibitors of the association between nuclear factor kappa B ( NF-κ B) and the corresponding κ B site in DNA. They were designed using the lead compound 15-deoxy-&UDelta;(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-κ B was unraveled by GOLD docking calculation. Subsequently, substitutions were made to PGJ2 to optimize its association with NF-κ 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-κ B. Density functional theory calculations were performed also to study the overall reactivity of the substituted drugs towards NF-κ 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-κ B, and their efficiency demonstrated by generating a set of substituted complexes, some of them with a very much increased affinity for NF-κ B, opening new doors to enlarge the therapeutic capabilities of this class of drugs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8