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.
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.
Piccagli
Laura
L
BioPharmaNet, ER-GenTech, Department of Biochemistry and Molecular Biology, University of Ferrara, Via Fossato di Mortara 74, 44100 Ferrara, Italy. laura.piccagli@unife.it
Fabbri
Enrica
E
Borgatti
Monica
M
Bianchi
Nicoletta
N
Bezzerri
Valentino
V
Mancini
Irene
I
Nicolis
Elena
E
Dechecchi
Cristina M
CM
Lampronti
Ilaria
I
Cabrini
Giulio
G
Gambari
Roberto
R
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D051841:Transcription Factor RelB / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D016209:Interleukin-8; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D051841:Transcription Factor RelB; D004247:DNA