Comparing Binding Stability of Gamma Glutamyl Cysteine to NF-κB and p۱۰۰ Using Molecular Dynamics Simulations and Free Energy Calculations with Implications for Anti-Covid-۱۹ Drug Design

Introduction: Nuclear factor κB (NF-κB) contributes to inflammation and cytokine storm in COVID-۱۹ patients. The NF-κB activity is inhibited by p۱۰۰ 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 p۱۰۰ 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 p۱۰۰. 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 p۱۰۰ and its slight structural changes in the presence of GGC. Analyzing amino acid fluctuations using RMSF revealed an important role of Leu ۴۵۰ and Phe ۴۵۱ in interactions of p۱۰۰ with GGC. Free binding energies of p۱۰۰-GGC and NF-κB-GGC complexes were -۶.۹۷۲ kJ/mol and ۲۵.۸۵۷ kJ/mol respectively. These results showed that GGC attached stably to p۱۰۰, 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 P۴۵۰ ۲C۹ 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 p۱۰۰ and enhancing p۱۰۰ activity for NF-κB inhibition. These results are useful for drug design against COVID-۱۹.

کلیدواژه ها:

COVID-۱۹ ، Gamma Glutamyl Cysteine ، Molecular Dynamics Simulation ، Nuclear Factor κB ، p۱۰۰/IκBδ ، Regulator