Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression

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• 作者：Laura Piccagli (1)
  Enrica Fabbri (1)
  Monica Borgatti (1)
  Valentino Bezzerri (2)
  Irene Mancini (3)
  Elena Nicolis (2)
  Maria C Dechecchi (2)
  Ilaria Lampronti (1)
  Giulio Cabrini (2)
  Roberto Gambari (1)
  
• 刊名：BMC Structural Biology
• 出版年：2008
• 出版时间：December 2008
• 年：2008
• 卷：8
• 期：1
• 全文大小：2675KB
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• 作者单位：Laura Piccagli (1)
  Enrica Fabbri (1)
  Monica Borgatti (1)
  Valentino Bezzerri (2)
  Irene Mancini (3)
  Elena Nicolis (2)
  Maria C Dechecchi (2)
  Ilaria Lampronti (1)
  Giulio Cabrini (2)
  Roberto Gambari (1)
  
  1. BioPharmaNet, ER-GenTech, Department of Biochemistry and Molecular Biology, University of Ferrara, Italy
  2. Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University-Hospital, Verona, Italy
  3. Department of Biochemistry and Molecular Biology, University of Ferrara, Italy
  
• ISSN：1472-6807

文摘

Background The transcription factor NF-kappaB is a very interesting target molecule for the design on anti-tumor, anti-inflammatory and pro-apoptotic drugs. However, the application of the widely-used molecular docking computational method for the virtual screening of chemical libraries on NF-kappaB is not yet reported in literature. Docking studies on a dataset of 27 molecules from extracts of two different medicinal plants to NF-kappaB-p50 were performed with the purpose of developing a docking protocol fit for the target under study. Results We enhanced the simple docking procedure by means of a sort of combined target- and ligand-based drug design approach. Advantages of this combination strategy, based on a similarity parameter for the identification of weak binding chemical entities, are illustrated in this work with the discovery of a new lead compound for NF-kappaB. Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score. All experimental analysis were in fairly good agreement with molecular modeling findings. Conclusion The results obtained sustain the concept that the docking performance is predictive of a biochemical activity. In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.