Development of a Structural Model for NF-κB Inhibition of Sesquiterpene Lactones Using Self-Organizing Neural Networks

Abstract

A variety of sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. Several studies have shown that they exert this effect in part by inhibiting the activation of the transcription factor NF-kappaB. In the present study we elaborated on the investigation of a data set of 103 structurally diverse SLs for which we had previously developed several different QSAR equations dependent on the skeletal type. Use of 3D structure descriptors resulted in a single model for the entire data set. In particular, local radial distribution functions (L-RDF) were used that centered on the methylene-carbonyl substructure believed to be the site of attack of cysteine-38 of the p65/NF-kappaB subunit. The model was developed by using a counterpropagation neural network (CPGNN), attesting to the power of this method for establishing structure-activity-relationships. The investigations shed more light onto the influence of the chemical structure on NF-kappaB inhibitory activity.

Inhibitors of NF-κB signaling: 785 and counting

“…Most SLs can also inhibit DNA binding by p50 and c-Rel through an analogous Cys residue in the DNA-binding loop, and mutations of this Cys residue to Ser generally make p50, RelA or c-Rel refractory to inhibition by such thiol-reactive compounds. Recently, a computer-based structural comparison of 103 SLs predicted that a methylene-carbonyl substructure is important for SL-based inhibition of RelA at Cys-38 (Wagner et al, 2006). Interestingly, some SLs, including the natural product parthenolide, have been shown to also inhibit IKKb through a reactive Cys residue (Cys-179), which is in the kinase activation loop (Kwok et al, 2001;Garcı´a-Pin˜eres et al, 2004).…”

In Silico‐Guided Strategies for the Discovery and Rationalization of Bioactive Natural Products

“…Wagner et al (2008) used an artificial neural network to develop a QSAR model that predicts the serotonin release inhibitory activity. In addition, the comparison of these descriptors with previously published ones used in an NF-B inhibition model (Wagner et al, 2006), provided information on the structural requirements of sesquiterpene lactones for the inhibition of serotonin release in contrast to NF-B inhibition.…”

Roles of the NFκB and glutathione pathways in mature human erythrocytes

“…The synthetic and lipophilic (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile (Bay 11-7082) blocks the kinase activity of IKK, thereby preventing IκB-α phosphorylation and degradation [9], and the sesquiterpene lactone (SL) and active component of the medical herb feverfew (Tanacetum parthenium) parthenolide blocks IKKα [10] and the NFκB subunit p65 (RelA) [11,12]. In addition, it could be shown that a methylene-carbonyl substructure is crucial for SL-based inhibition of RelA at cysteine 38 [13]. We treated erythrocytes with pharmacological doses of these inhibitors and found that both inhibitors were very effective inducers of programmed erythrocyte death, as characterized by phosphatidylserine (PS) exposure, cell shrinkage and elevation of intracellular Ca 2+ (Tab.…”