Comparing Binding Stability of Gamma Glutamyl Cysteine to NF-κB and p100 Using Molecular Dynamics Simulations and Free Energy Calculations with Implications for Anti-Covid-19 Drug Design

Ghaderi, Soheila; Tarahomjoo, Shirin

doi:10.30491/jabr.2024.403269.1649

Comparing Binding Stability of Gamma Glutamyl Cysteine to NF-κB and p100 Using Molecular Dynamics Simulations and Free Energy Calculations with Implications for Anti-Covid-19 Drug Design

Document Type : Original Article

Authors

Soheila Ghaderi

Shirin Tarahomjoo

Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran

10.30491/jabr.2024.403269.1649

Abstract

Introduction: Nuclear factor κB (NF-κB) contributes to inflammation and cytokine storm in COVID-19 patients. The NF-κB activity is inhibited by p100 protein binding and downregulated using glutathione. Gamma Glutamyl Cysteine (GGC) is also a glutathione precursor. In this study, we aim to compare GGC binding stability to p100 and NF-κB to elucidate its effectiveness in reducing NF-κB activity.
Materials and Methods: Tertiary structures were prepared by molecular graphics programs. Free binding energies of complexes were compared using molecular dynamics simulations and Auto Dock. Simulation outputs were analyzed using CMView.
Results: Analyzing RMSD values indicated quite stable binding of GGC to p100. Also, RMSD of the NF-κB-R complex was slightly lower than that of NF-κB at the simulation end. The Rg indicated less dense packing of p100 and its slight structural changes in the presence of GGC. Analyzing amino acid fluctuations using RMSF revealed an important role of Leu 450 and Phe 451 in interactions of p100 with GGC. Free binding energies of p100-GGC and NF-κB-GGC complexes were -6.972 kJ/mol and 25.857 kJ/mol respectively. These results showed that GGC attached stably to p100, whereas it did not bind to NF-κB. Contact maps of complexes and corresponding native structures were compared and slight structural changes were observed. The Interaction of P450 2C9 enzyme with GGC was more stable than that with Flurbiprophen.
Conclusions: According to the findings, we suggest an antiviral effect for GGC through its stable binding to p100 and enhancing p100 activity for NF-κB inhibition. These results are useful for drug design against COVID-19.

Keywords

COVID-19

Gamma Glutamyl Cysteine

Molecular Dynamics Simulation

Nuclear Factor κB

p100/IκBδ

Regulator