Cimicifugoside H-2 as an Inhibitor of IKK1/Alpha: A Molecular Docking and Dynamic Simulation Study

Abstract

One of the most challenging issues scientists face is finding a suitable non-invasive treatment for cancer, as it is widespread around the world. The efficacy of phytochemicals that target oncogenic pathways appears to be quite promising and has gained attention over the past few years. We investigated the effect of docking phytochemicals isolated from the rhizomes of the Cimicifuga foetida plant on different domains of the IκB kinase alpha (IKK1/alpha) protein. The Cimicifugoside H-2 phytochemical registered a high docking score on the activation loop of IKK1/alpha amongst the other phytochemicals compared to the positive control. The interaction of the protein with Cimicifugoside H-2 was mostly stabilized by hydrogen bonds and hydrophobic interactions. A dynamic simulation was then performed with the Cimicifugoside H-2 phytochemical on the activation loop of IKK1/alpha, revealing that Cimicifugoside H-2 is a possible inhibitor of this protein. The pharmacokinetic properties of the drug were also examined to assess the safety of administering the drug. Therefore, in this in silico study, we discovered that the Cimicifugoside H-2 phytochemical inhibits the actively mutated conformation of IKK1/alpha, potentially suppressing the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway.

Keywords: Cimicifugoside H-2; IKK1/alpha or IKK1/α; NF-κB pathway; dynamic simulation; molecular docking.

Figure 1

Molecular Docking of Cimicifugoside H-2 on IKK1/$\alpha$. (A) Surface representation of IKK1/$\alpha$ protein in blue and Cimicifugoside H-2 in magenta showing the interacting residues. (B) 2D diagram of protein–ligand interaction; hydrogen bonding is represented in green, and hydrophobic interactions are represented in pink.

Figure 2

Root Mean Square Deviation (RMSD) of IKK1/$\alpha$ protein in complex with Cimicifugoside H-2 during 100 ns of the molecular dynamic simulation period and Root Mean Squared of Fluctuation (RMSF) of IKK1/$\alpha$ protein both as unbound and in a complex with Cimicifugoside H-2.

Figure 3

Radius of Gyration (Rg) of IKK1/$\alpha$ protein both as unbound and in a complex with Cimicifugoside H-2.

Figure 4

Top 10 significant Enrichr MSigDB Hallmark 2020 proteins. The significantly expressed proteins have p ≤ 0.05. The brightness and the length of the bar represent the significance of the category/term.

Figure 5

Protein–protein interaction network of IKK1/$\mathsf{\alpha }$.

Figure 6

The canonical and non-canonical NF-$\mathsf{\kappa }$B pathways. The canonical pathway is activated by a wide range of receptors, such as the T-cell receptor (TCR), tumor necrosis factor receptor (TNFR), and interleukin-1 beta (IL-1$\mathsf{\beta }$). The receptors recruit multiple proteins to activate the transforming growth factor $\mathsf{\beta }-\mathrm{a}\mathrm{c}\mathrm{t}\mathrm{i}\mathrm{v}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{d}\mathrm{k}\mathrm{i}\mathrm{n}\mathrm{a}\mathrm{s}\mathrm{e}1$ (TAK1). TAK1 then mediates the phosphorylation and activation of IKK2/$\mathsf{\beta }$, making it available to associate with IKK1/$\mathsf{\alpha }$ and NEMO. This IKK complex then targets the substrate IkB$\mathsf{\alpha }$ for polyubiquitination phosphorylation, which results in its degradation. The p50:Rel A heterodimers are then formed, and they translocate to the nucleus to affect gene expression. However, in the non-canonical pathway, receptors such as cluster of differentiation 40 (CD40), B-cell activating factor receptor (BAFF), and lymphotoxin beta receptor ($\mathrm{L}\mathrm{T}\beta \mathrm{R}$), activate the nuclear factor kB-inducing kinase (NIK). NIK then phosphorylates and activates IKK1/$\mathsf{\alpha }$, which in turn process p100, leading to its polyubiquitination and degradation. This results in the formation of p52:Rel B, which promotes gene transcription in the nucleus.