title: Virtual screening against nuclear factor κB (NF-κB) of a focus library: Identification of bioactive furocoumarin derivatives inhibiting NF-κB dependent biological functions involved in cystic fibrosis.
abstract: In the present study, a structured-based virtual screening (VS) of differently substituted furocoumarins and analogues has been carried out against nuclear factor kappa B (NF-κB), with the objective of selecting molecules able to inhibit the binding of this transcription factor to the DNA. The focus library was developed starting from chemical structures obtained from the literature, as well as retrieving compounds from available commercial databases. A two dimensional substructure searching method based on four different chemical scaffolds was used for this purpose. Among the 10 highest-scored ligands selected from the docking studies, five commercially available molecules were investigated in biological assays. Four furocoumarin derivatives showed IC(50) values in the range of 40-100 μM in inhibiting NF-κB/DNA interactions studied by electrophoretic mobility shift assay (EMSA). Three compounds significantly inhibited NF-κB dependent biological functions (expression of IL-8) in cellular analysis based on Pseudomonas aeruginosa infection of cystic fibrosis IB3-1 cells. These findings validated the virtual screening approach here presented and reinforce the successful results of our previously computational studies aimed at the identification of molecules targeting NF-κB. The discovered novel compounds could be of relevance to identify more potent inhibitors of NF-κB dependent biological functions beneficial to control lung inflammation occurring in patients affected by cystic fibrosis.
authors.affiliation: BioPharmaNet, Department of Biochemistry and Molecular Biology, Interdisciplinary Center for the Study of Inflammation, Ferrara, Italy. laura.piccagli@unife.it
authors.forename: Laura
authors.initials: L
authors.lastname: Piccagli
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolis
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bianchi
authors.forename: Irene
authors.initials: I
authors.lastname: Mancini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.forename: Daniela
authors.initials: D
authors.lastname: Vevaldi
authors.forename: Francesco
authors.initials: F
authors.lastname: Dall'Acqua
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000378:metabolism*; D016208:Databases, Factual; D024202:Electrophoretic Mobility Shift Assay; D011564:Furocoumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D011564:Furocoumarins; D016209:Interleukin-8; D008024:Ligands; D016328:NF-kappa B