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Cimicifugoside H-2 as an Inhibitor of IKK1/Alpha: A Molecular Docking and Dynamic Simulation Study
Shahd Aboul Hosn1, Christina El Ahmadieh1, Sergio Thoumi2
1Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut Campus, P.O. Box 13-5053, Chouran, Beirut 1102 2801, Lebanon.
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.
Insights
Cimicifugoside H-2, a phytochemical from Cimicifuga foetida, shows potential as a non-invasive cancer treatment. This study found it inhibits IκB kinase alpha (IKK1/alpha), potentially blocking the NF-κB pathway.
Area of Science:
- Pharmacology
- Molecular Biology
- Computational Chemistry
Background:
- Non-invasive cancer treatments are crucial due to cancer's global prevalence.
- Phytochemicals targeting oncogenic pathways offer promising therapeutic avenues.
- Cimicifuga foetida rhizomes are a source of bioactive compounds.
Purpose of the Study:
- To investigate the inhibitory potential of Cimicifuga foetida phytochemicals against IκB kinase alpha (IKK1/alpha).
- To evaluate Cimicifugoside H-2 as a potential non-invasive cancer therapeutic agent.
- To explore the molecular interactions and pharmacokinetic properties of Cimicifugoside H-2.
Main Methods:
- In silico molecular docking of phytochemicals from Cimicifuga foetida against IKK1/alpha.
- Molecular dynamic simulations to analyze the stability of phytochemical-protein interactions.
- Pharmacokinetic property assessment for drug safety evaluation.
Main Results:
- Cimicifugoside H-2 exhibited a high docking score on the IKK1/alpha activation loop.
- Hydrogen bonds and hydrophobic interactions stabilized Cimicifugoside H-2 binding.
- Dynamic simulations confirmed Cimicifugoside H-2 as a potential IKK1/alpha inhibitor.
- Pharmacokinetic analysis suggested favorable safety profiles.
Conclusions:
- Cimicifugoside H-2 effectively inhibits the mutated conformation of IKK1/alpha.
- This inhibition may suppress the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway.
- Cimicifugoside H-2 represents a promising candidate for non-invasive cancer therapy.
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