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

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.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.The main aim of our molecular modelling investigations was to identify natural compounds for their ability to bind to the NF-kappaB p50 as a strategy to identify molecules exhibiting inhibitory activity on the molecular interactions of the transcription factor with its target DNA sequence. p50–p65 heterodimer is the predominant NF-kappaB complex in T-cells regulating HIV-1 infection and recent studies have shown that p50 unit of NF-kappaB is the one that mainly interacts with HIV-1 LTR [1,2]. The specific protein residues involved in DNA binding to the HIV-1 LTR NF-kappaB sites (sequence 5'-GGGACTTTCCC-3') have been identified [3,4]. Structurally different inhibitors of the NF-kappaB/DNA interactions with a rather low binding constant (in the range of 30 μM and 500 μM) are reported in the literature [5-7]. Recently, some molecular modelling studies have predicted possible binding mode of the inhibitors molecules to the DNA binding region of subunit p50, starting from the crystallographic structure of the NF-kappaB homodimer [6-9]