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In-silico screening of anti-cancer natural compounds targeting NF-κB as identification of potential therapeutic
Jarin Tasnim1, Md Mehedi Hasan1, Qandeel Fatima2
1Department of Applied Chemistry and Chemical Engineering, University of Rajshahi, Rajshahi, 6205 Bangladesh.
Abstract:
In the modern world, cancer is now one of the most significant causes of death. Nuclear factor-kappa B (NF-κB) is critical for inflammation and immune responses. Still, its abnormal activation or dysfunction can promote tumor cell proliferation and inhibit apoptosis, thereby initiating cancer progression. The objectives of this study are to discover the potential lead molecules with anti-cancer activity against NF-κB complexed with DNA (PDB ID: 1A3Q) through virtual screening based on the NPACT and containing 1574 anti-cancer natural compounds. All compounds were docked against 1A3Q using PyRx, and the first three molecules from the docking results were selected for further ADMET analysis using ADMETlab3.0 and Protox 3.0. The top three natural compounds were stable against NF-κB, had high GI absorption and low toxicity, and exhibited high binding affinities. One of these molecules (PubChem ID: 21600009) is drug-like for cancer, with a binding affinity of - 8.7 kcal/mol, which is why it was considered more significant than the other two compounds. Then, the best compound obtained from those calculations was included in GROMACS 2022.4 to evaluate its dynamic properties and interactions with the receptor. A simulation was carried out using the CHARMM36 force field and TIP3P water model. The electronic properties of the compound have also been calculated to confirm its drug-likeness using DFT at the B3LYP/6-31G(d,p) level in Gaussian 09. These comparative studies therefore indicate the potential of a cancer drug candidate that requires further experimental testing to verify its stability and biological efficacy.
Insights
This study identified potential anti-cancer drug candidates by virtually screening natural compounds targeting Nuclear Factor-kappa B (NF-κB). One compound shows promising drug-like properties and high binding affinity for further development.
Area of Science:
- Computational Chemistry
- Drug Discovery
- Molecular Biology
Background:
- Cancer is a leading cause of death globally.
- Nuclear Factor-kappa B (NF-κB) pathway dysregulation promotes cancer progression.
- Targeting NF-κB is a strategy for anti-cancer drug development.
Purpose of the Study:
- To identify novel anti-cancer lead molecules targeting the NF-κB complexed with DNA (PDB ID: 1A3Q).
- To virtually screen a library of 1574 anti-cancer natural compounds.
- To evaluate the drug-likeness and binding affinity of potential candidates.
Main Methods:
- Virtual screening using PyRx and docking against PDB ID: 1A3Q.
- ADMET analysis using ADMETlab3.0 and Protox 3.0 for top candidates.
- Molecular dynamics simulations with GROMACS and electronic property calculations using DFT.
Main Results:
- Identified three natural compounds with high binding affinities and stability against NF-κB.
- One compound (PubChem ID: 21600009) demonstrated significant drug-like properties and a binding affinity of -8.7 kcal/mol.
- Dynamic simulations and electronic property calculations confirmed the compound's stability and drug-likeness.
Conclusions:
- The study identified a promising drug candidate for cancer therapy targeting NF-κB.
- The identified compound exhibits favorable ADMET properties and high binding affinity.
- Further experimental validation is recommended to confirm the compound's efficacy and stability.
